Compounds for treatment of diseases of abnormal angiogenesis or aberrant growth factors and uses thereof

ABSTRACT

The present invention provides novel compounds of any one of Formulae (I)-(IV), and pharmaceutical compositions thereof. Also provided are particles (e.g., nanoparticles) comprising compounds of any one of Formulae (I)-(IV) and pharmaceutical compositions thereof that are mucus penetrating. The invention also provides methods and kits for using the inventive compounds, and pharmaceutical compositions thereof, for treating and/or preventing diseases associated with abnormal or pathological angiogenesis and/or aberrant signaling of a growth factor signaling pathway (e.g., vascular endothelial growth factor (VEGF)), such as proliferative diseases (e.g., cancers, benign neoplasms, inflammatory diseases, autoimmune diseases) and ocular diseases (e.g., macular degeneration, glaucoma, diabetic retinopathy, retinoblastoma, edema, uveitis, dry eye, blepharitis, and post-surgical inflammation) in a subject in need thereof.

BACKGROUND OF THE INVENTION

Growth factors play an important role in angiogenesis,lymphangiogenesis, and vasculogenesis. Growth factors regulateangiogenesis in a variety of processes including embryonic development,wound healing, and several aspects of female reproductive function.Undesirable or pathological angiogenesis is associated with diseasesincluding diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis,atheroma, Kaposi's sarcoma, and hemangioma (Fan et al., 1995, TrendsPharmacol. Sci. 16: 57 66; Folkman, 1995, Nature Medicine 1: 27 31).Angiogenic ocular conditions represent the leading cause of irreversiblevision loss in developed countries. In the United States, for example,retinopathy of prematurity, diabetic retinopathy, and age-relatedmacular degeneration are the principal causes of blindness in infants,working age adults, and the elderly, respectively. Efforts have beendeveloped to inhibit angiogenesis in the treatment of these conditions(R. Roskoski Jr., Critical Reviews in Oncology/Hematology, 62 (2007),179-213).

Therefore, there is a need for new therapeutic compounds for thetreatment of diseases associated with the aberrant signaling of growthfactors and diseases associated with angiogenesis, such as cancer,macular degeneration, and diabetic retinopathy.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of Formulae (I)-(IV), andpharmaceutical compositions thereof, and kits useful in treating and/orpreventing diseases associated with abnormal angiogenesis and/oraberrant signaling of a growth factor (e.g., vascular endothelial growthfactor (VEGF)). The diseases that may be treated and/or prevented by theinventive compounds, pharmaceutical compositions, kits, uses, andmethods include proliferative diseases (e.g., cancers, benign neoplasms,inflammatory diseases, autoimmune diseases) and ocular diseases (e.g.,macular degeneration, glaucoma, diabetic retinopathy, retinoblastoma,edema, uveitis, dry eye, blepharitis, and post-surgical inflammation).

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein X, Y, Ring A, Ring Y, R^(A), R^(B), R^(C),R^(D), R^(L), a, l, and m are as defined herein.

Exemplary compounds of Formula (I) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein U, V, W, Ring Z, R^(E), R^(F), R^(G),R^(H), R^(J), R^(M), p, and n are as defined herein.

An exemplary compound of Formula (II) is:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In yet another aspect, the present invention provides the compound ofFormula (III):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In still another aspect, the present invention provides the compound ofFormula (IV):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In still another aspect, the present invention provides pharmaceuticalcompositions including a compound of the invention, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical compositions described herein include an effective amountof a compound of the invention. The pharmaceutical composition may beuseful for treating proliferative diseases (e.g., cancers, benignneoplasms, inflammatory diseases, autoimmune diseases) and/or oculardiseases (e.g., macular degeneration, glaucoma, diabetic retinopathy,retinoblastoma, edema, uveitis, dry eye, blepharitis, and post-surgicalinflammation) in a subject in need thereof. The pharmaceuticalcomposition may also be useful for inhibiting abnormal angiogenesisand/or aberrant signaling of a growth factor in a subject or cell.

In some embodiments, the compounds described herein may be intended fordelivery in a subject's tissues having mucus (e.g., eye, respiratorytract, gastrointestinal tract, genito-urinary tract), which is aviscoelastic and adhesive substance that traps most foreign objects(e.g., microorganisms, particles, dust). For effective drug delivery,compound or particles that are immobilized in the mucus are quicklyeliminated by mucus clearance mechanisms; therefore, they are not ableto effectively deliver the intended therapeutic effect. In thesetissues, for the compound to effective, it must quickly penetrate themucus and/or avoid mucus clearance mechanisms. Accordingly, modifyingmucoadhesive compounds or particles containing compounds with a coatingto reduce the mucoadhesiveness, and decreasing the size of the particlesof compound may allow for efficient delivery and therapeutic effect.

In one aspect of the invention, the compounds described herein areformulated into mucus penetrating particles or mucus penetratingcrystals (collectively, MPPs) suitable for administration (e.g., topicalor inhalation) to tissues of the subject having mucus (e.g., eye,respiratory tract, gastrointestinal tract, genito-urinary tract). Incertain embodiments, the inventive compounds are crystalline.

In another aspect, the present invention provides particles containing acompound described herein or particles comprising a compound describedherein. In certain embodiments, the particles are mucus penetrating. Theparticles of the invention may include a coating surrounding a core. Thecore may contain primarily a compound of the invention, or the core maybe a polymeric core with the compound encapsulated in the polymer. Incertain embodiments, the inventive particles are nanoparticles (e.g.,particles having an average diameter of at least about 10 nm and lessthan about 1 μm). The inventive particles may be useful in deliveringthe pharmaceutical agent to a subject. In certain embodiments, theparticles of the invention are capable of delivering the pharmaceuticalagent in or through mucus of a subject.

Another aspect of the invention relates to pharmaceutical compositionscomprising an inventive compound and/or a plurality of inventiveparticles. In certain embodiments, the pharmaceutical compositions areuseful in delivering a pharmaceutical agent (e.g., the compound of theinvention) to a subject.

In another aspect of the invention, the present invention providespharmaceutical composition comprising a plurality of particlescomprising (i) a core comprising a compound of the invention describedherein, or a pharmaceutically acceptable salt thereof, and (ii) acoating of a surface altering agent surrounding the core, wherein thesurface altering agent is present on the outer surface of the core at adensity of at least 0.01 surface altering agent per nm², and optionally,at least one pharmaceutically acceptable excipient. In some embodiments,the surface altering agent is a triblock copolymer of the structure(hydrophilic block)-(hydrophobic block)-(hydrophilic block). In someaspects, the triblock copolymer is a Pluronic, poloxamer, poly(vinylalcohol), or a polysorbate.

In certain embodiments, the compound, particle, or pharmaceuticalcomposition is formulated to be mucus penetrating.

Another aspect of the present invention relates to methods of treatingand/or preventing a disease associated with abnormal angiogenesis in asubject in need thereof.

Another aspect of the present invention relates to methods of treatingand/or preventing a disease associated with aberrant signaling of agrowth factor signaling pathway in a subject in need thereof.

In another aspect, the present invention provides methods of inhibitingangiogenesis in a subject in need thereof.

In another aspect, the present invention provides methods of inhibitingaberrant signaling of a growth factor signaling pathway in a subject orcell. In certain embodiments, the growth factor is associated withangiogenesis. In certain embodiments, the growth factor is VEGF.

The methods of the present invention include administering to thesubject an effective amount of a compound or pharmaceutical compositionof the invention. In certain embodiments, the effective amount is atherapeutically effective amount. In certain embodiments, the effectiveamount is a prophylactically effective amount.

Another aspect of the invention relates to methods of screening alibrary of compounds to identify one or more compounds that are usefulin the methods of the invention (e.g., inhibiting abnormalangiogenesis).

In yet another aspect, the present invention provides compounds andpharmaceutical compositions of the invention for use in the treatmentand/or prevention of a disease associated with abnormal angiogenesisand/or associated with aberrant signaling of a growth factor signalingpathway in a subject in need thereof.

Another aspect of the present invention relates to kits comprising acontainer with a compound or pharmaceutical composition of theinvention. The kits of the invention may include a single dose ormultiple doses of the inventive compound, or pharmaceutical compositionsthereof. The provided kits may be useful in treating and/or preventing adisease associated with abnormal angiogenesis and/or with aberrantsignaling of a growth factor in a subject in need thereof. The kits mayalso be useful for inhibiting abnormal angiogenesis and/or aberrantsignaling of a growth factor signaling pathway in a subject in needthereof. In certain embodiments, the kit further includes instructionsfor administering the compound, or pharmaceutical composition, to thesubject.

The present application refers to various issued patent, publishedpatent applications, journal articles, and other publications, all ofwhich are incorporated herein by reference.

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the Figures, the Examples, andthe Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N.Y., 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₆ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group. In certain embodiments, the aralkyl isoptionally substituted benzyl. In certain embodiments, the aralkyl isbenzyl. In certain embodiments, the aralkyl is optionally substitutedphenethyl. In certain embodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4 n+2 aromatic ring system (e.g., having 6 or 10 p electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Partially unsaturated” refers to a group that includes at least onedouble or triple bond. A “partially unsaturated” ring system is furtherintended to encompass rings having multiple sites of unsaturation, butis not intended to include aromatic groups (e.g., aryl or heteroarylgroups) as herein defined. Likewise, “saturated” refers to a group thatdoes not contain a double or triple bond, i.e., contains all singlebonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, which are divalent bridging groups arefurther referred to using the suffix—ene, e.g., alkylene, alkenylene,alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene.

As used herein, the term “optionally substituted” refers to substitutedor unsubstituted.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; or two geminalhydrogens on a carbon atom are replaced with the group ═O, ═S,═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

-   -   each instance of R^(bb) is, independently, selected from        hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),        —C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),        —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),        —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),        —P(═O)₂R, —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,        C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,        C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and        5-14 membered heteroaryl, or two R^(bb) groups are joined to        form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl        ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,        heterocyclyl, aryl, and heteroaryl is independently substituted        with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NRCO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR)OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR)OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents canbe joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” as used herein refers to a moiety selected from the groupconsisting of —C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or—C(═S)SR^(aa), wherein R^(aa) and R^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substituents include, but are not limitedto, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc), and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anitrogen protecting group (also referred to as an amino protectinggroup). Nitrogen protecting groups include, but are not limited to, —OH,—OR, —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aralkyl, aryl, and heteroaryl is independently substitutedwith 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb),R^(cc) and R^(dd) are as defined herein. Nitrogen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamante, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, t-butyloxycarbonyl (BOC or Boc), methoxylmethyl (MOM),methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec),2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate,alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenylcarbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate,alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate,alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R, —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

These and other exemplary substituents are described in more detail inthe Detailed Description, Figures, Examples, and Claims. The inventionis not intended to be limited in any manner by the above exemplarylisting of substituents.

Other Definitions

The following definitions are more general terms used throughout thepresent application.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds described herein may be prepared, e.g., incrystalline form, and may be solvated. Suitable solvates includepharmaceutically acceptable solvates and further include bothstoichiometric solvates and non-stoichiometric solvates. In certaininstances, the solvate will be capable of isolation, for example, whenone or more solvent molecules are incorporated in the crystal lattice ofa crystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, and methanolates.

The term “hydrate” refers to a compound which is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2H₂O) and hexahydrates (R.6H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertable compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof) in a particular crystal packingarrangement. All polymorphs have the same elemental composition.Different crystalline forms usually have different X-ray diffractionpatterns, infrared spectra, melting points, density, hardness, crystalshape, optical and electrical properties, stability, and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate. Variouspolymorphs of a compound can be prepared by crystallization underdifferent conditions.

The term “prodrugs” refer to compounds, including derivatives of thecompounds described herein, which have cleavable groups and become bysolvolysis or under physiological conditions the compounds describedherein, which are pharmaceutically active in vivo. Such examplesinclude, but are not limited to, choline ester derivatives and the like,N-alkylmorpholine esters and the like. Other derivatives of thecompounds of this invention have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds of this invention are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds(e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female at any stage of development. The animalmay be a transgenic animal or genetically engineered animal. In certainembodiments, the subject is non-human animal. In certain embodiments,the animal is fish. A “patient” refers to a human subject in need oftreatment of a disease.

The terms “administer,” “administering,” or “administration,” as usedherein, refers to implanting, absorbing, ingesting, injecting, inhaling,or otherwise introducing an inventive compound, or a pharmaceuticalcomposition thereof, in or on a subject.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease described herein. In some embodiments, treatmentmay be administered after one or more signs or symptoms of the diseasehave developed or have been observed. In other embodiments, treatmentmay be administered in the absence of signs or symptoms of the disease.For example, treatment may be administered to a susceptible subjectprior to the onset of symptoms (e.g., in light of a history of symptomsand/or in light of exposure to a pathogen). Treatment may also becontinued after symptoms have resolved, for example, to delay or preventrecurrence.

As used herein, the terms “condition,” “disease,” and “disorder” areused interchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent. In certain embodiments, a “therapeuticallyeffective amount” of a compound or composition is the amount needed toinhibit angiogenesis in a subject.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “protein” or “peptide” comprises a polymer of amino acid residueslinked together by peptide bonds. The term, as used herein, refers toproteins, polypeptides, and peptides of any size, structure, orfunction. Typically, a protein will be at least three amino acids long.A protein may refer to an individual protein or a collection ofproteins. Inventive proteins preferably contain only natural aminoacids, although non-natural amino acids (i.e., compounds that do notoccur in nature but that can be incorporated into a polypeptide chain)and/or amino acid analogs as are known in the art may alternatively beemployed. Also, one or more of the amino acids in an inventive proteinmay be modified, for example, by the addition of a chemical entity suchas a carbohydrate group, a hydroxyl group, a phosphate group, a famesylgroup, an isofarnesyl group, a fatty acid group, a linker forconjugation or functionalization, or other modification. A protein mayalso be a single molecule or may be a multi-molecular complex. A proteinmay be a fragment of a naturally occurring protein or peptide. A proteinmay be naturally occurring, recombinant, synthetic, or any combinationof these.

As used herein, the term “growth factor” refers to a naturally occurringsubstance (e.g., a protein or a steroid hormone) capable of stimulatingcellular growth, proliferation, and cellular differentiation. Growthfactors may act as signaling molecules between cells and/or promote celldifferentiation and maturation.

As used herein, the term “vascular endothelial growth factor” or “VEGF”refers to a signal protein produced by cells that stimulatevasculogenesis and angiogenesis. VEGFs are a sub-family of growthfactors, i.e., the platelet-derived growth factor family of cystine-knotgrowth factors. VEGFs are important signaling proteins involved in bothvasculogenesis and angiogenesis. VEGFs' normal function is to create newblood vessels during embryonic development, new blood vessels afterinjury, muscle following exercise, and new vessels (collateralcirculation) to bypass blocked vessels. When VEGF is overexpressed, itcan contribute to a range of diseases, such as proliferative diseases(e.g., cancer) and vascular diseases in the retina of the eye and otherparts of the body. VEGFs include a number of proteins from two familiesthat result from alternate splicing of mRNA from a single, 8-exon, VEGFgene. Examples of VEGFs include, but are not limited to, VEGF-relatedproteins such as placental growth factor (PGF), VEGF-A, VEGF-B, VEGF-C,VEGF-D, VEGF-E, and VEGF-F. The term “VEGF” also encompasses VEGFreceptors (VEGFRs), such as VEGFR-1, VEGFR-2 and VEGFR-3. A VEGFR may bemembrane-bound (mbVEGFR) or soluble (sVEGFR).

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, andautoimmune diseases.

As used herein, the term “angiogenesis” refers to the physiologicalprocess through which new blood vessels form from pre-existing vessels.Angiogenesis is distinct from vasculogenesis, which is the de novoformation of endothelial cells from mesoderm cell precursors. The firstvessels in a developing embryo form through vasculogenesis, after whichangiogenesis is responsible for most blood vessel growth during normalor abnormal development. Angiogenesis is a vital process in growth anddevelopment, as well as in wound healing and in the formation ofgranulation tissue. However, angiogenesis is also a fundamental step inthe transition of tumors from a benign state to a malignant one, leadingto the use of angiogenesis inhibitors in the treatment of cancer.Angiogenesis may be chemically stimulated by angiogenic proteins, suchas growth factors (e.g., VEGF).

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue.

As used herein, the term “cancer” refers to a malignant neoplasm(Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990). Exemplary cancers include, but are not limited to,acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer;angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma,hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliarycancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g.,adenocarcinoma of the breast, papillary carcinoma of the breast, mammarycancer, medullary carcinoma of the breast); brain cancer (e.g.,meningioma, glioblastomas, glioma (e.g., astrocytoma,oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor;cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma;chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer,rectal cancer, colorectal adenocarcinoma); connective tissue cancer;epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi'ssarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer(e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarinoma); Ewing'ssarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastictumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastomaa.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g.,hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g.,bronchogenic carcinoma, small cell lung cancer (SCLC), non-small celllung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS);mastocytosis (e.g., systemic mastocytosis); muscle cancer;myelodysplastic syndrome (MDS); mesothelioma; myeloproliferativedisorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreaticneuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer(e.g., Paget's disease of the penis and scrotum); pinealoma; primitiveneuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplasticsyndromes; intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

As used herein, the term “inflammatory disease” or “inflammation” refersto a disease caused by, resulting from, or resulting in inflammation.The term “inflammatory disease” may also refer to a dysregulatedinflammatory reaction that causes an exaggerated response bymacrophages, granulocytes, and/or T-lymphocytes leading to abnormaltissue damage and/or cell death. An inflammatory disease can be eitheran acute or chronic inflammatory condition and can result frominfections or non-infectious causes. Inflammatory diseases include,without limitation, atherosclerosis, arteriosclerosis, autoimmunedisorders, multiple sclerosis, systemic lupus erythematosus, polymyalgiarheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis,bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoidarthritis, inflammatory arthritis, Sjogren's syndrome, giant cellarteritis, progressive systemic sclerosis (scleroderma), ankylosingspondylitis, polymyositis, dermatomyosifis, pemphigus, pemphigoid,diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroditis,Graves' disease, Goodpasture's disease, mixed connective tissue disease,sclerosing cholangitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, pernicious anemia, inflammatory dermatoses, usualinterstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis,berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamativeinterstitial pneumonia, lymphoid interstitial pneumonia, giant cellinterstitial pneumonia, cellular interstitial pneumonia, extrinsicallergic alveolitis, Wegener's granulomatosis and related forms ofangiitis (temporal arteritis and polyarteritis nodosa), inflammatorydermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g.,poison ivy dermatitis), pneumonia, respiratory tract inflammation, AdultRespiratory Distress Syndrome (ARDS), encephalitis, immediatehypersensitivity reactions, asthma, hayfever, allergies, acuteanaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury),reperfusion injury, allograft rejection, host-versus-graft rejection,appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,cervicitis, cholangitis, chorioamnionitis, conjunctivitis,dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis,myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis,urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis,vulvovaginitis, angitis, chronic bronchitis, osteomylitis, opticneuritis, temporal arteritis, transverse myelitis, necrotizingfascilitis, and necrotizing enterocolitis. Ocular inflammatory diseasesinclude, but are not limited to, allergy of the eye, uveitis (e.g.,anterior uveitis, intermediate uveitis, and posterior uveitis),conjunctivitis, panuveitis, cyclitis, scleritis, episcleritis, opticneuritis, retrobulbar optic neuritis, keratitis (e.g., immune keratitisand infectious keratitis), blepharitis, corneal ulcer, conjunctivalulcer and symptoms caused by them, ocular inflammatory diseases causedby ocular disorders, ocular inflammatory diseases caused by a physicalinjury, post-surgical inflammation, and dry eye (e.g., dry eyesyndrome).

As used herein, an “autoimmune disease” refers to a disease arising froman inappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodspature's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid, arthritis, psoriatic arthritis,systemic lupus erythematosis, psoriasis, ulcerative colitis, systemicsclerosis, dermatomyositis/polymyositis, anti-phospholipid antibodysyndrome, scleroderma, perphigus vulgaris, ANCA-associated vasculitis(e.g., Wegener's granulomatosis, microscopic polyangiitis), urveitis,Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosingspondylitis, Lyme arthritis, GuillainBarre syndrome, Hashimoto'sthyroiditis, and cardiomyopathy.

The term “ocular disease” or “ocular disorder” refers to any eye diseaseand/or disorder. For example, ocular diseases can be disorders of theeyelid, lacrimal system and orbit, disorders of conjunctiva, disordersof sclera, cornea, iris and ciliary body, disorders of choroid andretina, glaucoma, disorders of optic nerve and visual pathways, occularyinflammatory diseases, or disorders of ocular muscles. Additionally,ocular disease can also refer to discomfort following injury, surgery,or laser treatment. Diseases and disorders of the eye include, but arenot limited to, macular degeneration, dry eye syndrome, uveitis,allergic conjunctivitis, glaucoma, and rosacea (of the eye). Dry eyesyndrome (DES), otherwise known as keratoconjunctivitis sicca (KCS),keratitis sicca, sicca syndrome, or xerophthalmia, is an eye diseasecaused by decreased tear production or increased tear film evaporationcommonly found in humans and some animals

The term “age-related macular degeneration” or “AMD” is an oculardisease which usually affects older adults and results in a loss ofvision in the center of the visual field (the macula) because of damageto the retina. It occurs in “dry” and “wet” forms. It is a major causeof blindness and visual impairment in older adults (>50 years). Maculardegeneration can make it difficult or impossible to read or recognizefaces, although enough peripheral vision remains to allow otheractivities of daily life. The macula is the central area of the retina,which provides the most detailed central vision. In the dry(nonexudative) form, cellular debris called drusen accumulate betweenthe retina and the choroid, and the retina can become detached. In thewet (exudative) form, which is more severe, blood vessels grow up fromthe choroid behind the retina, and the retina can also become detached.It can be treated with laser coagulation, and with medication that stopsand sometimes reverses the growth of blood vessels. Although somemacular dystrophies affecting younger subjects are sometimes referred toas macular degeneration, the term generally refers to age-relatedmacular degeneration (AMD or ARMD). AMD begins with characteristicyellow deposits (drusen) in the macula, between the retinal pigmentepithelium and the underlying choroid. Most patients with these earlychanges (referred to as age-related maculopathy) have good vision.Patients with drusen can go on to develop advanced AMD. The risk isconsiderably higher when the drusen are large and numerous andassociated with disturbance in the pigmented cell layer under themacula. Recent research suggests that large and soft drusen are relatedto elevated cholesterol deposits and may respond to cholesterol-loweringagents.

The term “macular edema” refers to ocular disease cystoid macular edema(CME) or diabetic macular edema (DME). CME is an ocular disease whichaffects the central retina or macula of the eye. When this condition ispresent, multiple cyst-like (cystoid) areas of fluid appear in themacula and cause retinal swelling or edema. CME may accompany a varietyof diseases such as retinal vein occlusion, uveitis, and/or diabetes.CME commonly occurs after cataract surgery. DME occurs when bloodvessels in the retina of patients with diabetes begin to leak into themacula, the part of the eye responsible for detailed central vision.These leaks cause the macula to thicken and swell, progressivelydistorting acute vision. While the swelling may not lead to blindness,the effect can cause a severe loss in central vision.

The term “glaucoma” refers to an ocular disease in which the optic nerveis damaged in a characteristic pattern. This can permanently damagevision in the affected eye and lead to blindness if left untreated. Itis normally associated with increased fluid pressure in the eye (aqueoushumor). The term ocular hypertension is used for patients withconsistently raised intraocular pressure (IOP) without any associatedoptic nerve damage. Conversely, the term normal tension or low tensionglaucoma is used for those with optic nerve damage and associated visualfield loss but normal or low IOP. The nerve damage involves loss ofretinal ganglion cells in a characteristic pattern. There are manydifferent subtypes of glaucoma, but they can all be considered to be atype of optic neuropathy. Raised intraocular pressure (e.g., above 21mmHg or 2.8 kPa) is the most important and only modifiable risk factorfor glaucoma. However, some may have high eye pressure for years andnever develop damage, while others can develop nerve damage at arelatively low pressure. Untreated glaucoma can lead to permanent damageof the optic nerve and resultant visual field loss, which over time canprogress to blindness.

The term “uveitis” refers to an inflammatory disease of the uvea, thevascular layer of the eye sandwiched between the retina and the white ofthe eye (sclera). The uvea extends toward the front of the eye andconsists of the iris, choroid layer and ciliary body. Uveitis includesanterior uveitis, intermediate uveitis, and posterior uveitis. A commontype of uveitis is an inflammation of the iris called iritis (anterioruveitis). Uveitis may also occur at the posterior segment of the eye(e.g., at the choroid). Inflammation of the uvea can be recurring andcan cause serious problems such as blindness if left untreated (accountsfor 10% of blindness globally). Early diagnosis and treatment areimportant to prevent the complications of uveitis.

The term “dry eye” or “dry eyes” refers to an ocular disease in whichthere are insufficient tears to lubricate and nourish the eye. Tears arenecessary for maintaining the health of the front surface of the eye andfor providing clear vision. Patients with dry eyes either do not produceenough tears or have a poor quality of tears. Dry eye is a common andoften chronic problem, particularly in older adults. With each blink ofthe eyelids, tears are spread across the front surface of the eye, knownas the cornea. Tears provide lubrication, reduce the risk of eyeinfection, wash away foreign matter in the eye, and keep the surface ofthe eyes smooth and clear. Excess tears in the eyes flow into smalldrainage ducts, in the inner corners of the eyelids, which drain in theback of the nose. Tears are produced by several glands (e.g., lacrimalgland) in and around the eyelids. Tear production tends to diminish withage, with various medical conditions, or as a side effect of certainmedicines. Environmental conditions such as wind and dry climates canalso affect tear volume by increasing tear evaporation. When the normalamount of tear production decreases or tears evaporate too quickly fromthe eyes, symptoms of dry eye can develop. The most common form of dryeyes is due to an inadequate amount of the water layer of tears. Thiscondition, called keratoconjunctivitis sicca (KCS), is also referred toas “dry eye syndrome.” A non-limiting example of dry eye syndrome isSjögren's syndrome.

The term “diabetic retinopathy” refers to retinopathy (i.e., a diseaseof the retina) caused by complications of diabetes, which can eventuallylead to blindness. Diabetic retinopathy may cause no symptoms, mildvision problems, or even blindness. Diabetic retinopathy is the resultof microvascular retinal changes. Hyperglycemia-induced intramuralpericyte death and thickening of the basement membrane lead toincompetence of the vascular walls. These damages change the formationof the blood-retinal barrier and also make the retinal blood vesselsbecome more permeable. The pericyte death is caused when “hyperglycemiapersistently activates protein kinase C-δ (PKC-δ, encoded by Prkcd) andp38 mitogen-activated protein kinase (MAPK) to increase the expressionof a previously unknown target of PKC-δ signaling, Src homology-2domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase.This signaling cascade leads to PDGF receptor-dephosphorylation and areduction in downstream signaling from this receptor, resulting inpericyte apoptosis. Small blood vessels, such as those in the eye, areespecially vulnerable to poor control over blood sugar. Anoveraccumulation of glucose and/or fructose damages the tiny bloodvessels in the retina. During the initial stage, called“nonproliferative diabetic retinopathy” (NPDR), most patients do notnotice any change in their vision. Early changes that are reversible anddo not threaten central vision are sometimes termed simplex retinopathyor background retinopathy. As the disease progresses, severenonproliferative diabetic retinopathy enters an advanced, “proliferativediabetic retinopathy” (PDR) stage when blood vessels proliferate. Thelack of oxygen in the retina causes fragile, new, blood vessels to growalong the retina and in the clear, gel-like vitreous humor that fillsthe inside of the eye, which may result in bleeding, cloud vision,retina damage, or tractional retinal detachment.

The term “particle” refers to a small object, fragment, or piece of asubstance that may be a single element, inorganic material, organicmaterial, or mixture thereof. Examples of particles include polymericparticles, single-emulsion particles, double-emulsion particles,coacervates, liposomes, microparticles, nanoparticles, macroscopicparticles, pellets, crystals (e.g., crystalline forms of compounds oractive pharmaceutical agent), aggregates, composites, pulverized,milled, or otherwise disrupted matrices, and cross-linked protein orpolysaccharide particles, each of which have an average characteristicdimension of about less than about 1 mm and at least 1 nm, where thecharacteristic dimension, or “critical dimension,” of the particle isthe smallest cross-sectional dimension of the particle. A particle maybe composed of a single substance or multiple substances. In certainembodiments, the particle is not a viral particle. In other embodiments,the particle is not a liposome. In certain embodiments, the particle isnot a micelle. In certain embodiments, the particle is substantiallysolid throughout. In certain embodiments, the particle is ananoparticle. In certain embodiments, the particle is a microparticle.

The term “nanoparticle” refers to a particle having a characteristicdimension of less than about 1 micrometer and at least about 1nanometer, where the characteristic dimension of the particle is thesmallest cross-sectional dimension of the particle. A crystallinenanoparticle is referred to as a “nanocrystal.”

The term “microparticle” refers to a particle having a characteristicdimension of less than about 1 millimeter and at least about 1micrometer, where the characteristic dimension of the particle is thesmallest cross-sectional dimension of the particle.

The term “nanostructure” refers to a structure having at least oneregion or characteristic dimension with a dimension of less than about1000 nm, e.g., less than about 300 nm, less than about 200 nm, less thanabout 100 nm, or less than about 50 nm. Typically, the region orcharacteristic dimension will be along the smallest axis of thestructure. Examples of such structures include nanowires, nanorods,nanotubes, branched nanocrystals, nanotetrapods, tripods, bipods,nanocrystals, nanodots, quantum dots, nanoparticles, branched tetrapods(e.g., inorganic dendrimers), and the like. Nanostructures can besubstantially homogeneous in material properties, or in certainembodiments can be heterogeneous (e.g. heterostructures). Nanostructurescan be, e.g., substantially crystalline, substantially monocrystalline,polycrystalline, amorphous, or a combination thereof. In one aspect,each of the three dimensions of the nanostructure has a dimension ofless than about 1000 nm, e.g., or even less than about 300 nm, less thanabout 200 nm, less than about 100 nm, or less than about 50 nm.Nanostructures can comprise one or more surface ligands (e.g.,surfactants).

The terms “crystalline” or “substantially crystalline”, when used withrespect to nanostructures, refer to the fact that the nanostructurestypically exhibit long-range ordering across one or more dimensions ofthe structure. It will be understood by one of skill in the art that theterm “long range ordering” will depend on the absolute size of thespecific nanostructures, as ordering for a single crystal cannot extendbeyond the boundaries of the crystal. In this case, “long-rangeordering” will mean substantial order across at least the majority ofthe dimension of the nanostructure. In some instances, a nanostructurecan bear an oxide or other coating, or can be comprised of a core and atleast one shell. In such instances it will be appreciated that theoxide, shell(s), or other coating need not exhibit such ordering (e.g.it can be amorphous, polycrystalline, or otherwise). In such instances,the phrase “crystalline,” “substantially crystalline,” “substantiallymonocrystalline,” or “monocrystalline” refers to the central core of thenanostructure (excluding the coating layers or shells). The terms“crystalline” or “substantially crystalline” as used herein are intendedto also encompass structures comprising various defects, stackingfaults, atomic substitutions, and the like, as long as the structureexhibits substantial long range ordering (e.g., order over at leastabout 80% of the length of at least one axis of the nanostructure or itscore). In addition, it will be appreciated that the interface between acore and the outside of a nanostructure or between a core and anadjacent shell or between a shell and a second adjacent shell maycontain non-crystalline regions and may even be amorphous. This does notprevent the nanostructure from being crystalline or substantiallycrystalline as defined herein. The term “monocrystalline” when used withrespect to a nanostructure indicates that the nanostructure issubstantially crystalline and comprises substantially a single crystal.When used with respect to a nanostructure heterostructure comprising acore and one or more shells, “monocrystalline” indicates that the coreis substantially crystalline and comprises substantially a singlecrystal. When not used with respect to a nanostructure, the term“monocrystalline” to materials that are composed of substantially asingle crystallite of substantially the same size and orientation.

“Nanocrystal” is a nanostructure that is substantially monocrystalline.A nanocrystal thus has at least one region or characteristic dimensionwith a dimension of less than about 1000 nm, e.g., less than about 300nm less than about 200 nm, less than about 100 nm, or less than about 50nm. Typically, the region or characteristic dimension will be along thesmallest axis of the structure. Examples of such structures includenanowires, nanorods, nanotubes, branched nanowires, nanotetrapods,nanotripods, nanobipods, nanocrystals, nanodots, quantum dots,nanoparticles, nanoribbons, and the like. Nanostructures can besubstantially homogeneous in material properties, or in certainembodiments can be heterogeneous (e.g. heterostructures). Optionally, ananocrystal can comprise one or more surface ligands (e.g.,surfactants). The nanocrystal is optionally substantially single crystalin structure (a “single crystal nanostructure” or a “monocrystallinenanostructure”). While nanostructures for use in the present inventioncan be fabricated from essentially any convenient material or material,preferably the nanostructure is prepared from an inorganic material,e.g., an inorganic conductive or semiconductive material. A conductiveor semi-conductive nanostructure often displays 1-dimensional quantumconfinement, e.g., an electron can often travel along only one dimensionof the structure. Nanocrystals can be substantially homogeneous inmaterial properties, or in certain embodiments can be heterogeneous(e.g. heterostructures). The term “nanocrystal” is intended to encompasssubstantially monocrystalline nanostructures comprising various defects,stacking faults, atomic substitutions, and the like, as well assubstantially monocrystalline nanostructures without such defects,faults, or substitutions. In the case of nanocrystal heterostructurescomprising a core and one or more shells, the core of the nanocrystal istypically substantially monocrystalline, but the shell(s) need not be.The nanocrystals can be fabricated from essentially any convenientmaterial or materials.

The term “polycrystalline” refers to materials that are composed of manycrystallites of varying size and orientation. When used with respect tonanostructures, the term “polycrystalline” refers to a crystallinenanostructure that is not monocrystalline.

A “biocompatible” material refers to a material that does not typicallyinduce an adverse response when inserted or injected into a subject. Theadverse response includes significant inflammation and/or acuterejection of the material by the immune system of the subject, forinstance, via a T-cell-mediated response. It is recognized that“biocompatibility” is a relative term and that some degree of immuneresponse is to be expected even for materials that are highly compatiblewith living tissues of the subject. However, as used herein,“biocompatibility” refers to the acute rejection of a material by atleast a portion of the immune system, i.e., a material that lacksbiocompatibility (i.e. being non-biocompatible) in a subject provokes animmune response in the subject that is severe enough such that therejection of the material by the immune system cannot be adequatelycontrolled and often is of a degree such that the material must beremoved from the subject in order for the subject to be as well as itwas before the non-biocompatible material was introduced into thesubject. One test to determine biocompatibility of a material is toexpose the material to cells (e.g., fibroblasts or epithelial cells) invitro; the material is considered biocompatible if it does not result insignificant cell death at moderate concentrations, e.g., atconcentrations of about 50 micrograms/10⁶ cells. In certain embodiments,there is no significant cell death if less than about 20% of the cellsare dead, even if phagocytosed or otherwise uptaken by the cells. Insome embodiments, a material is biocompatible if contacting it withcells in vitro results in less than 20% cell death and if theadministration of the material in vivo does not induce unwantedinflammation or other adverse responses. In certain embodiments, abiocompatible material is biodegradable. A non-limiting example ofbiocompatible materials is biocompatible polymers (includingbiocompatible copolymers).

A “biodegradable” material refers to a material that is able to degradechemically and/or biologically (e.g., by hydrolysis or enzymaticactivity), within a physiological environment, such as within the bodyor when introduced to cells. For instance, the material may be one thathydrolyzes spontaneously upon exposure to water (e.g., within a subject)and/or may degrade upon exposure to heat (e.g., at temperatures of about37° C.). Degradation of a material may occur at varying rates, dependingon the material used. For example, the half-life of the material (thetime at which 50% of the material is degraded into smaller components)may be on the order of days, weeks, months, or years. The material maybe biologically degraded, e.g., by enzymatic activity or cellularmachinery, for example, through exposure to a lysozyme. In someembodiments, the material may be broken down into smaller componentsthat cells can either reuse or dispose of without significant toxiceffect on the cells (e.g., fewer than about 20% of the cells are killedwhen the components are added to cells in vitro). Non-limiting examplesof biodegradable materials are biodegradable polymers (includingbiodegradable copolymers). Examples of biodegradable polymers include,but are not limited to, poly(ethylene glycol)-poly(propyleneoxide)-poly(ethylene glycol) triblock copolymers, poly(vinyl alcohol)(PVA), poly(lactide) (or poly(lactic acid)), poly(glycolide) (orpoly(glycolic acid)), poly(orthoesters), poly(caprolactones),polylysine, poly(ethylene imine), poly(acrylic acid), poly(urethanes),poly(anhydrides), poly(esters), poly(trimethylene carbonate),poly(ethyleneimine), poly(acrylic acid), poly(urethane), poly(beta aminoesters), and copolymers thereof (e.g., poly(lactide-co-glycolide)(PLGA)).

As used herein, the terms “pharmaceutical composition” and “formulation”are used interchangeably.

As used herein, the terms “pharmaceutical agent” and “drug” are usedinterchangeably.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The present invention provides novel compounds of Formulae (I)-(IV). Theinvention also provides pharmaceutical compositions including theinventive compounds and kits including the inventive compounds orcompositions thereof useful in treating and/or preventing diseasesassociated with abnormal angiogenesis and/or aberrant signaling of agrowth factor pathway (e.g., vascular endothelial growth factor (VEGF)).The diseases that may be treated and/or prevented using the inventivecompounds, pharmaceutical compositions, kits, uses, and methods includeproliferative diseases (e.g., cancers, benign neoplasms, inflammatorydiseases, autoimmune diseases) and ocular diseases (e.g., maculardegeneration, glaucoma, diabetic retinopathy, retinoblastoma, edema,uveitis, dry eye, blepharitis, and post-surgical inflammation).

Compounds

The present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof;

-   -   wherein:

X is a bond, —C(═O)—, —S(═O)—, or —S(═O)₂—;

Y is a bond, —C(═O)—, —S(═O)—, or —S(═O)₂—;

Ring A is substituted or unsubstituted, 4- to 7-membered, monocyclicheterocyclyl, or substituted or unsubstituted, 7- to 10-membered, spirobicyclic heterocyclyl, wherein one or two atoms in the heterocyclic ringare independently selected from the group consisting of oxygen andnitrogen;

Ring Y is substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

each instance of R^(A) is independently hydrogen, halogen, substitutedor unsubstituted alkyl, —OR^(A1), —N(R^(A1))₂, oxo, or a nitrogenprotecting group when attached to a nitrogen atom;

each instance of R^(A1) is independently hydrogen, substituted orunsubstituted alkyl, a nitrogen protecting group when attached to anitrogen atom, or an oxygen protecting group when attached to an oxygenatom, or two instances of R^(A1) are joined to form substituted orunsubstituted heterocyclyl;

a is 0, 1, 2, or 3;

R^(B) is substituted or unsubstituted alkyl or of the formula:

Ring B is substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

each instance of R^(B1) is independently hydrogen, halogen, substitutedor unsubstituted acyl, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(B1a), —N(R^(B1a))₂, —SR^(B1a), —CN, —SCN,—C(═NR^(B1a))R^(B1a), —C(═NR^(B1a))OR^(B1a), C(═NR^(B1a))N(R^(B1a))₂,—C(═O)R^(B1a), —C(═O)OR^(B1a), —C(═O)N(R^(B1a))₂, —NO₂,—NR^(B1a)C(═O)R^(B1a), —NR^(B1a)C(═O)OR^(B1a),—NR^(B1a)C(═O)N(R^(B1a))₂, —OC(═O)R^(B1a), —OC(═O)OR^(B1a),OC(═O)N(R^(B1a))₂, or a nitrogen protecting group when attached to anitrogen atom, or two instances of R^(B1) are joined to form substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;

each instance of R^(B1a) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(B1a) are joined to form substituted or unsubstituted heterocyclyl;

-   -   b is 0, 1, 2, 3, 4, or 5;

R^(C) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

R^(D) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group; each instance of R^(L) is independentlyhydrogen, halogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(L1), —N(R^(L1))₂,—SR^(L1), —CN, —SCN, —C(═NR^(L1))R^(L1), —C(═NR)OR^(L1),—C(═NR^(L1))N(R^(L1))₂, —C(═O)R^(L1), —C(═O)OR^(L1), —C(═O)N(R^(L1))₂,—NO₂, —NR^(L1)C(═O)R^(L), —NR^(L1)C(═O)OR^(L1), —NR^(L1)C(═O)N(R^(L1))₂,—OC(═O)R^(L1), —OC(═O)OR^(L1), or —OC(═O)N(R^(L1))₂, or two instances ofR^(L) are joined to form substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;

each instance of R^(L1) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(L1) are joined to form substituted or unsubstituted heterocyclyl;

l is 0, 1, 2, 3, or 4; and

m is 0, 1, 2, 3, 4, or 5.

Compounds of Formula (I) include moiety X. In certain embodiments, X isa bond. In certain embodiments, X is a single bond. In certainembodiments, X is —C(═O)—. In certain embodiments, X is —S(═O)—. Incertain embodiments, X is —S(═O)₂—.

Compounds of Formula (I) include moiety Y. In certain embodiments, Y isa bond. In certain embodiments, Y is a single bond. In certainembodiments, Y is —C(═O)—. In certain embodiments, Y is —S(═O)—. Incertain embodiments, Y is —S(═O)₂—.

In certain embodiments, each one of X and Y is a bond. In certainembodiments, X is a bond; and Y is —C(═O)—, —S(═O)—, or —S(═O)₂—. Incertain embodiments, X is —C(═O)—, —S(═O)—, or —S(═O)₂—; and Y is abond. In certain embodiments, each one of X and Y is independently—C(═O)—, —S(═O)—, or —S(═O)₂—. In certain embodiments, X is a bond; andY is —C(═O)—. In certain embodiments, X is —C(═O)—; and Y is a bond. Incertain embodiments, each one of X and Y is —C(═O)—.

Compounds of Formula (I) include Ring A that is attached to Y. Incertain embodiments, Ring A is substituted or unsubstituted, 4- to7-membered, monocyclic heterocyclyl, wherein one or two atoms in theheterocyclic ring are independently oxygen or nitrogen. In certainembodiments, Ring A is substituted or unsubstituted, 4- to 6-membered,monocyclic heterocyclyl, wherein one atom in the heterocyclic ring isoxygen. In certain embodiments, Ring A is substituted oxetanyl. Incertain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is unsubstituted oxetanyl. In certainembodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is substituted tetrahydrofuranyl. Incertain embodiments, Ring A is unsubstituted tetrahydrofuranyl. Incertain embodiments, Ring A is substituted tetrahydropyranyl. In certainembodiments, Ring A is unsubstituted tetrahydropyranyl. In certainembodiments, Ring A is substituted or unsubstituted, 4- to 7-membered,monocyclic heterocyclyl, wherein one atom in the heterocyclic ring isnitrogen. In certain embodiments, Ring A is substituted pyrrolidinyl. Incertain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

wherein at least one R^(A1) is substituted alkyl. In certainembodiments, Ring A is of the formula:

wherein at least one R^(A1) is unsubstituted alkyl. In certainembodiments, Ring A is of the formula:

wherein at least one R^(A1) is unsubstituted C₁₋₆ alkyl. In certainembodiments, Ring A is unsubstituted pyrrolidinyl. In certainembodiments, Ring A is of the formula:

In certain embodiments, Ring A is substituted piperidinyl. In certainembodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is unsubstituted piperidinyl. In certainembodiments, Ring A is of the formula:

In certain embodiments, Ring A is substituted or unsubstituted, 7- to10-membered, spiro bicyclic heterocyclyl, wherein two atoms in theheterocyclic ring are independently selected from the group consistingof oxygen and nitrogen. In certain embodiments, Ring A is of theformula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of a formula:

In certain embodiments, Ring A is of the formula:

Compounds of Formula (I) may include one or more substituents R^(A) onRing A. In certain embodiments, at least one instance of R^(A) is H. Incertain embodiments, at least one instance of R^(A) is halogen. Incertain embodiments, at least one instance of R^(A) is F. In certainembodiments, at least one instance of R^(A) is Cl. In certainembodiments, at least one instance of R^(A) is Br. In certainembodiments, at least one instance of R^(A) is I (iodine). In certainembodiments, at least one instance of R^(A) is substituted alkyl. Incertain embodiments, at least one instance of R^(A) is unsubstitutedalkyl. In certain embodiments, at least one instance of R^(A) is C₁₋₁₂alkyl. In certain embodiments, at least one instance of R^(A) is C₁₋₆alkyl. In certain embodiments, at least one instance of R^(A) isunsubstituted methyl. In certain embodiments, at least one instance ofR^(A) is substituted methyl. In certain embodiments, at least oneinstance of R^(A) is —CH₂F. In certain embodiments, at least oneinstance of R^(A) is —CHF₂. In certain embodiments, at least oneinstance of R^(A) is —CF₃. In certain embodiments, at least one instanceof R^(A) is Bn. In certain embodiments, at least one instance of R^(A)is unsubstituted ethyl. In certain embodiments, at least one instance ofR^(A) is substituted ethyl. In certain embodiments, at least oneinstance of R^(A) is —(CH₂)₂Ph. In certain embodiments, at least oneinstance of R^(A) is substituted or unsubstituted propyl. In certainembodiments, at least one instance of R^(A) is substituted orunsubstituted butyl. In certain embodiments, at least one instance ofR^(A) is substituted or unsubstituted pentyl. In certain embodiments, atleast one instance of R^(A) is substituted or unsubstituted hexyl. Incertain embodiments, at least one instance of R^(A) is halogen orunsubstituted C₁₋₆ alkyl. In certain embodiments, at least one instanceof R^(A) is —OR^(A1). In certain embodiments, at least one instance ofR^(A) is —OR^(A1), wherein R^(A1) is substituted alkyl. In certainembodiments, at least one instance of R^(A) is —OR^(A1), wherein R^(A1)is unsubstituted alkyl. In certain embodiments, at least one instance ofR^(A) is —OR^(A1), wherein R^(A1) is substituted C₁₋₆ alkyl. In certainembodiments, at least one instance of R^(A) is —OR^(A1), wherein R^(A1)is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(A) is —OPh. In certain embodiments, at least one instanceof R^(A) is —OBn. In certain embodiments, at least one instance of R^(A)is —O(CH₂)₂Ph. In certain embodiments, at least one instance of R^(A) is—OH. In certain embodiments, at least one instance of R^(A) is—N(R^(A1))₂. In certain embodiments, at least one instance of R^(A) is—N(R^(A1))₂, wherein at least one instance of R^(A1) is substitutedalkyl. In certain embodiments, at least one instance of R^(A) is—N(R^(A1))₂, wherein at least one instance of R^(A1) is unsubstitutedalkyl. In certain embodiments, at least one instance of R^(A) is—N(R^(A1))₂, wherein at least one instance of R^(A1) is substituted C₁₋₆alkyl. In certain embodiments, at least one instance of R^(A) is—N(R^(A1))₂, wherein at least one instance of R^(A1) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, at least one instance of R^(A) is—NH₂. In certain embodiments, at least one instance of R^(A) is oxo(═O). In certain embodiments, at least one instance of R^(A) is anitrogen protecting group when attached to a nitrogen atom. In certainembodiments, at least one instance of R^(A) is Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to anitrogen atom.

In certain embodiments, at least one instance of R^(A1) is H. In certainembodiments, at least one instance of R^(A1) is substituted alkyl. Incertain embodiments, at least one instance of R^(A1) is unsubstitutedalkyl. In certain embodiments, at least one instance of R^(A1) issubstituted C₁₋₆ alkyl. In certain embodiments, at least one instance ofR^(A1) is unsubstituted C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(A1) is unsubstituted methyl. In certain embodiments, atleast one instance of R^(A1) is substituted methyl. In certainembodiments, at least one instance of R^(A1) is —CH₂F. In certainembodiments, at least one instance of R^(A1) is —CHF₂. In certainembodiments, at least one instance of R^(A1) is —CF₃. In certainembodiments, at least one instance of R^(A1) is Bn. In certainembodiments, at least one instance of R^(A1) is unsubstituted ethyl. Incertain embodiments, at least one instance of R^(A1) is substitutedethyl. In certain embodiments, at least one instance of R^(A1) is—(CH₂)₂Ph. In certain embodiments, at least one instance of R^(A1) ispropyl. In certain embodiments, at least one instance of R^(A1) isbutyl. In certain embodiments, at least one instance of R^(A1) ispentyl. In certain embodiments, at least one instance of R^(A1) ishexyl. In certain embodiments, at least one instance of R^(A1) is anitrogen protecting group when attached to a nitrogen atom. In certainembodiments, at least one instance of R^(A1) is Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to anitrogen atom. In certain embodiments, at least one instance of R^(A1)is an oxygen protecting group when attached to an oxygen atom. Incertain embodiments, at least one instance of R^(A1) is silyl, TBDPS,TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, orbenzoyl when attached to an oxygen atom.

In certain embodiments, two instances of R^(A1) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(A1) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(A1) are joinedto form heterocyclyl including one, two, or three double bonds in thering of the heterocyclyl. In certain embodiments, two instances ofR^(A1) are joined to form heterocyclyl, wherein one, two, or three atomsin the ring of the heterocyclyl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. In certainembodiments, two instances of R^(A1) are joined to form 3- to7-membered, monocyclic heterocyclyl. In certain embodiments, twoinstances of R^(A1) are joined to form 5- to 13-membered, bicyclicheterocyclyl.

In certain embodiments, a is 0. In certain embodiments, a is 1. Incertain embodiments, a is 2. In certain embodiments, a is 3.

In certain embodiments, R^(A) is —N(R^(A1))₂; and a is 1. In certainembodiments, R^(A) is —N(unsubstituted C₁₋₆ alkyl)₂; and a is 1. Incertain embodiments, R^(A) is oxo (═O); and a is 1.

Compounds of Formula (I) include Ring Y. In certain embodiments, Ring Yis substituted carbocyclyl. In certain embodiments, Ring Y isunsubstituted carbocyclyl. In certain embodiments, Ring Y is saturatedcarbocyclyl. In certain embodiments, Ring Y is unsaturated carbocyclyl.In certain embodiments, Ring Y is carbocyclyl including one, two, orthree double bonds in the carbocyclic ring. In certain embodiments, RingY is monocyclic carbocyclyl. In certain embodiments, Ring Y is 3- to7-membered, monocyclic carbocyclyl. In certain embodiments, Ring Y issubstituted cylcopropyl. In certain embodiments, Ring Y is unsubstitutedcylcopropyl. In certain embodiments, Ring Y is cyclobutyl. In certainembodiments, Ring Y is cyclopentyl. In certain embodiments, Ring Y iscyclohexyl. In certain embodiments, Ring Y is cycloheptyl. In certainembodiments, Ring Y is bicyclic carbocyclyl. In certain embodiments,Ring Y is 5- to 13-membered, bicyclic carbocyclyl.

In certain embodiments, Ring Y is substituted heterocyclyl. In certainembodiments, Ring Y is unsubstituted heterocyclyl. In certainembodiments, Ring Y is saturated heterocyclyl. In certain embodiments,Ring Y is unsaturated heterocyclyl. In certain embodiments, Ring Y isheterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, Ring Y is heterocyclyl,wherein one, two, or three atoms in the heterocyclic ring areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, Ring Y is monocyclic heterocyclyl.In certain embodiments, Ring Y is 3- to 7-membered, monocyclicheterocyclyl. In certain embodiments, Ring Y is 5-membered, monocyclicheterocyclyl. In certain embodiments, Ring Y is substituted orunsubstituted tetrahydrofuranyl. In certain embodiments, Ring Y is6-membered, monocyclic heterocyclyl. In certain embodiments, Ring Y issubstituted or unsubstituted tetrahydropyranyl. In certain embodiments,Ring Y is bicyclic heterocyclyl. In certain embodiments, Ring Y is 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, Ring Y is substituted aryl. In certainembodiments, Ring Y is unsubstituted aryl. In certain embodiments, RingY is 6- to 14-membered aryl. In certain embodiments, Ring Y is 6- to10-membered aryl. In certain embodiments, Ring Y is unsubstitutedphenyl. In certain embodiments, Ring Y is substituted phenyl. In certainembodiments, Ring Y is of the formula:

In certain embodiments, Ring Y is of the formula:

In certain embodiments, Ring Y is of the formula:

In certain embodiments, Ring Y is substituted heteroaryl. In certainembodiments, Ring Y is unsubstituted heteroaryl. In certain embodiments,Ring Y is 5- to 6-membered, monocyclic heteroaryl, wherein one, two,three, or four atoms in the heteroaryl ring are independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, Ring Y is 5-membered, monocyclic heteroaryl. In certainembodiments, Ring Y is 5-membered, monocyclic heteroaryl, wherein one ofthe five atoms in the heteroaryl ring is nitrogen, oxygen, or sulfur.

Compounds of Formula (I) include substituent R^(B). In certainembodiments, R^(B) is substituted alkyl. In certain embodiments, R^(B)is unsubstituted alkyl. In certain embodiments, R^(B) is substitutedC₁₋₆ alkyl. In certain embodiments, R^(B) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(B) is unsubstituted methyl. In certainembodiments, R^(B) is substituted methyl. In certain embodiments, R^(B)is —CH₂F. In certain embodiments, R^(B) is —CHF₂. In certainembodiments, R^(B) is —CF₃. In certain embodiments, R^(B) is Bn. Incertain embodiments, R^(B) is unsubstituted ethyl. In certainembodiments, R^(B) is substituted ethyl. In certain embodiments, R^(B)is —(CH₂)₂Ph. In certain embodiments, R^(B) is propyl. In certainembodiments, R^(B) is butyl. In certain embodiments, R^(B) isunsubstituted t-butyl. In certain embodiments, R^(B) is pentyl. Incertain embodiments, R^(B) is hexyl.

In certain embodiments, R^(B) is of the formula:

In certain embodiments, Ring B is substituted carbocyclyl. In certainembodiments, Ring B is unsubstituted carbocyclyl. In certainembodiments, Ring B is saturated carbocyclyl. In certain embodiments,Ring B is unsaturated carbocyclyl. In certain embodiments, Ring B iscarbocyclyl including one, two, or three double bonds in the carbocyclicring. In certain embodiments, Ring B is monocyclic carbocyclyl. Incertain embodiments, Ring B is 3- to 7-membered, monocyclic carbocyclyl.In certain embodiments, Ring B is substituted cylcopropyl. In certainembodiments, Ring B is unsubstituted cylcopropyl. In certainembodiments, Ring B is cyclobutyl. In certain embodiments, Ring B iscyclopentyl. In certain embodiments, Ring B is cyclohexyl. In certainembodiments, Ring B is cycloheptyl. In certain embodiments, Ring B isbicyclic carbocyclyl. In certain embodiments, Ring B is 5- to13-membered, bicyclic carbocyclyl.

In certain embodiments, Ring B is substituted heterocyclyl. In certainembodiments, Ring B is unsubstituted heterocyclyl. In certainembodiments, Ring B is saturated heterocyclyl. In certain embodiments,Ring B is unsaturated heterocyclyl. In certain embodiments, Ring B isheterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, Ring B is heterocyclyl,wherein one, two, or three atoms in the heterocyclic ring areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, Ring B is monocyclic heterocyclyl.In certain embodiments, Ring B is 3- to 7-membered, monocyclicheterocyclyl. In certain embodiments, Ring B is 5-membered, monocyclicheterocyclyl. In certain embodiments, Ring B is substituted orunsubstituted tetrahydrofuranyl. In certain embodiments, Ring B is6-membered, monocyclic heterocyclyl. In certain embodiments, Ring B issubstituted or unsubstituted tetrahydropyranyl. In certain embodiments,Ring B is bicyclic heterocyclyl. In certain embodiments, Ring B is 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, Ring B is substituted aryl. In certainembodiments, Ring B is unsubstituted aryl. In certain embodiments, RingB is 6- to 14-membered aryl. In certain embodiments, Ring B is 6- to10-membered aryl. In certain embodiments, Ring B is unsubstitutedphenyl. In certain embodiments, Ring B is substituted phenyl. In certainembodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is substituted naphthyl. In certainembodiments, Ring B is unsubstituted naphthyl.

In certain embodiments, Ring B is substituted heteroaryl. In certainembodiments, Ring B is unsubstituted heteroaryl. In certain embodiments,Ring B is 5- to 6-membered, monocyclic heteroaryl, wherein one, two,three, or four atoms in the heteroaryl ring are independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, Ring B is 5-membered, monocyclic heteroaryl. In certainembodiments, Ring B is 5-membered, monocyclic heteroaryl, wherein one ofthe five atoms in the heteroaryl ring is nitrogen, oxygen, or sulfur. Incertain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is 5-membered, monocyclic heteroaryl,wherein two of the five atoms in the heteroaryl ring are independentlynitrogen, oxygen, or sulfur. In certain embodiments, Ring B is of theformula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is 5-membered, monocyclic heteroaryl,wherein only three of the five atoms in the heteroaryl ring areindependently nitrogen, oxygen, or sulfur. In certain embodiments, RingB is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is 5-membered, monocyclic heteroaryl,wherein four of the five atoms in the heteroaryl ring are nitrogen,oxygen, or sulfur. In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is 6-membered, monocyclic heteroaryl,wherein one, two, or three atoms in the heteroaryl ring are nitrogen. Incertain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is a bicyclic heteroaryl moiety, whereinthe point of attachment may be on any atom of the bicyclic heteroarylring system, as valency permits. In certain embodiments, Ring B issubstituted bicyclic heteroaryl. In certain embodiments, Ring B isunsubstituted bicyclic heteroaryl. In certain embodiments, Ring B is 9-or 10-membered, bicyclic heteroaryl, wherein one, two, three, or fouratoms in the bicyclic ring of the heteroaryl moiety are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, Ring B is 8- to 10-membered, bicyclic heteroaryl,wherein one atom in the bicyclic ring of the heteroaryl moiety isnitrogen, oxygen, or sulfur. In certain embodiments, Ring B is 8- to10-membered, bicyclic heteroaryl, wherein two atoms in the bicyclic ringof the heteroaryl moiety are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, RingB is 8- to 10-membered, bicyclic heteroaryl, wherein three atoms in thebicyclic ring of the heteroaryl moiety are independently selected fromthe group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, Ring B is 8- to 10-membered, bicyclic heteroaryl, whereinfour atoms in the bicyclic ring of the heteroaryl moiety areindependently selected from the group consisting of nitrogen, oxygen,and sulfur.

In certain embodiments, R^(B) is t-butyl. In certain embodiments, R^(B)is cyclopropyl. In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

In certain embodiments, R^(B) is of the formula:

When R^(B) is of the formula:

compounds of Formula (I) may include one or more substituents R^(B). Incertain embodiments, at least one instance of R^(B1) is H. In certainembodiments, at least one instance of R^(B1) is halogen. In certainembodiments, at least one instance of R^(B1) is F. In certainembodiments, at least one instance of R^(B1) is Cl. In certainembodiments, at least one instance of R^(B1) is Br. In certainembodiments, at least one instance of R^(B1) is I (iodine). In certainembodiments, at least one instance of R^(B1) is substituted acyl. Incertain embodiments, at least one instance of R^(B1) is unsubstitutedacyl. In certain embodiments, at least one instance of R^(B1) issubstituted alkyl. In certain embodiments, at least one instance ofR^(B1) is unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(B1) is C₁₋₁₂ alkyl. In certain embodiments, at least oneinstance of R^(B1) is C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(B1) is unsubstituted methyl. In certain embodiments, atleast one instance of R^(B1) is substituted methyl. In certainembodiments, at least one instance of R^(B1) is CH₂F. In certainembodiments, at least one instance of R^(B1) is CHF₂. In certainembodiments, at least one instance of R^(B1) is CF₃. In certainembodiments, at least one instance of R^(B1) is CH₂N(R^(B1a))₂. Incertain embodiments, at least one instance of R^(B1) isCH₂N(unsubstituted C₁₋₆ alkyl)(CH₂)₂₋₄—OH. In certain embodiments, atleast one instance of R^(B1) is CH₂N(CH₃)(CH₂)₂—OH. In certainembodiments, at least one instance of R^(B1) is of the formula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is—CH²—NH(R^(B1a)). In certain embodiments, at least one instance ofR^(B1) is —CH₂—NH(unsubstituted C₁₋₆ alkyl). In certain embodiments, atleast one instance of R^(B1) is —CH₂—NH(CH₃). In certain embodiments, atleast one instance of R^(B1) is Bn. In certain embodiments, at least oneinstance of R^(B1) is unsubstituted ethyl. In certain embodiments, atleast one instance of R^(B1) is substituted ethyl. In certainembodiments, at least one instance of R^(B1) is —(CH₂)₂Ph. In certainembodiments, at least one instance of R^(B1) is propyl. In certainembodiments, at least one instance of R^(B1) is butyl. In certainembodiments, at least one instance of R^(B1) is pentyl. In certainembodiments, at least one instance of R^(B1) is hexyl. In certainembodiments, at least one instance of R^(B1) is halogen or substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(B1) is substituted alkenyl. In certain embodiments, atleast one instance of R^(B1) is unsubstituted alkenyl. In certainembodiments, at least one instance of R^(B1) is vinyl. In certainembodiments, at least one instance of R^(B1) is substituted alkynyl. Incertain embodiments, at least one instance of R^(B1) is unsubstitutedalkynyl. In certain embodiments, at least one instance of R^(B1) isethynyl. In certain embodiments, at least one instance of R^(B1) issubstituted carbocyclyl. In certain embodiments, at least one instanceof R^(B1) is unsubstituted carbocyclyl. In certain embodiments, at leastone instance of R^(B1) is saturated carbocyclyl. In certain embodiments,at least one instance of R^(B1) is unsaturated carbocyclyl. In certainembodiments, at least one instance of R^(B1) is carbocyclyl includingone, two, or three double bonds in the carbocyclic ring. In certainembodiments, at least one instance of R^(B1) is monocyclic carbocyclyl.In certain embodiments, at least one instance of R^(B1) is 3- to7-membered, monocyclic carbocyclyl. In certain embodiments, at least oneinstance of R^(B1) is cylcopropyl. In certain embodiments, at least oneinstance of R^(B1) is cyclobutyl. In certain embodiments, at least oneinstance of R^(B1) is cyclopentyl. In certain embodiments, at least oneinstance of R^(B1) is cyclohexyl. In certain embodiments, at least oneinstance of R^(B1) is cycloheptyl. In certain embodiments, at least oneinstance of R^(B1) is bicyclic carbocyclyl. In certain embodiments, atleast one instance of R^(B1) is 5- to 13-membered, bicyclic carbocyclyl.In certain embodiments, at least one instance of R^(B1) is substitutedheterocyclyl. In certain embodiments, at least one instance of R^(B1) isunsubstituted heterocyclyl. In certain embodiments, at least oneinstance of R^(B1) is saturated heterocyclyl. In certain embodiments, atleast one instance of R^(B1) is unsaturated heterocyclyl. In certainembodiments, at least one instance of R^(B1) is heterocyclyl includingone, two, or three double bonds in the heterocyclic ring. In certainembodiments, at least one instance of R^(B1) is heterocyclyl, whereinone, two, or three atoms in the heterocyclic ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, at least one instance of R^(B1) is monocyclicheterocyclyl. In certain embodiments, at least one instance of R^(B1) is3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, atleast one instance of R^(B1) is of the formula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certainembodiments, at least one instance of R^(B1) is of the formula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is bicyclicheterocyclyl. In certain embodiments, at least one instance of R^(B1) is5- to 13-membered, bicyclic heterocyclyl. In certain embodiments, atleast one instance of R^(B1) is substituted aryl. In certainembodiments, at least one instance of R^(B1) is unsubstituted aryl. Incertain embodiments, at least one instance of R^(B1) is 6- to14-membered aryl. In certain embodiments, at least one instance ofR^(B1) is 6- to 10-membered aryl. In certain embodiments, at least oneinstance of R^(B1) is substituted phenyl. In certain embodiments, atleast one instance of R^(B1) is unsubstituted phenyl. In certainembodiments, at least one instance of R^(B1) is substituted naphthyl. Incertain embodiments, at least one instance of R^(B1) is unsubstitutednaphthyl. In certain embodiments, at least one instance of R^(B1) issubstituted heteroaryl. In certain embodiments, at least one instance ofR^(B1) is unsubstituted heteroaryl. In certain embodiments, at least oneinstance of R^(B1) is heteroaryl, wherein one, two, three, or four atomsin the heteroaryl ring are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one instance of R^(B1) is monocyclic heteroaryl. In certainembodiments, at least one instance of R^(B1) is 5-membered, monocyclicheteroaryl. In certain embodiments, at least one instance of R^(B1) isof the formula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is 6-membered,monocyclic heteroaryl. In certain embodiments, at least one instance ofR^(B1) is pyridyl. In certain embodiments, at least one instance ofR^(B1) is bicyclic heteroaryl, wherein the point of attachment may be onany atom of the bicyclic heteroaryl ring system, as valency permits. Incertain embodiments, at least one instance of R^(B1) is 9-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(B1) is of the formula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is 10-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(B1) is —OR^(B1a). In certain embodiments, at least one instance ofR^(B1) is —OMe. In certain embodiments, at least one instance of R^(B1)is —OEt. In certain embodiments, at least one instance of R^(B1) is—OPr. In certain embodiments, at least one instance of R^(B1) is —OBu.In certain embodiments, at least one instance of R^(B1) is —O(pentyl).In certain embodiments, at least one instance of R^(B1) is —O(hexyl). Incertain embodiments, at least one instance of R^(B1) is —OPh. In certainembodiments, at least one instance of R^(B1) is —OBn. In certainembodiments, at least one instance of R^(B1) is —O(CH₂)₂Ph. In certainembodiments, at least one instance of R^(B1) is —OH. In certainembodiments, at least one instance of R^(B1) is —O—CF₃. In certainembodiments, at least one instance of R^(B1) is —O—(CH₂)₂₋₄—N(R^(B1a))₂.In certain embodiments, at least one instance of R^(B1) is—O—(CH₂)₂₋₄—N(unsubstituted C₁₋₆ alkyl)₂. In certain embodiments, atleast one instance of R^(B1) is —O—(CH₂)₂—N(CH₃)₂. In certainembodiments, at least one instance of R^(B1) is —O—(CH₂)₃—N(CH₃)₂. Incertain embodiments, at least one instance of R^(B1) is of the formula:

In certain embodiments, at least one instance of R is of the formula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is of theformula:

In certain embodiments, at least one instance of R^(B1) is —SR^(B1a). Incertain embodiments, at least one instance of R^(B1) is —SH. In certainembodiments, at least one instance of R^(B1) is —N(R^(B1a))₂. In certainembodiments, at least one instance of R^(B1) is —NH₂. In certainembodiments, at least one instance of R^(B1) is —CN. In certainembodiments, at least one instance of R^(B1) is —SCN. In certainembodiments, at least one instance of R^(B1) is —C(═NR^(B1a))R^(B1a),—C(═NR^(B1a))OR^(B1a), or —C(═NR^(B1a))N(R^(B1a))₂. In certainembodiments, at least one instance of R^(B1) is —C(═O)R^(B1a),—C(═O)OR^(B1a), or —C(═O)N(R^(B1a))₂. In certain embodiments, at leastone instance of R^(B1) is —NO₂. In certain embodiments, at least oneinstance of R^(B1) is —NR^(B1a)C(═O)R^(B1a), —NR^(B1a)C(═O)OR^(B1a), or—NR^(B1a)C(═O)N(R^(B1a))₂. In certain embodiments, at least one instanceof R^(B1) is —OC(═O)R^(B1a), —OC(═O)OR^(B1a), or —OC(═O)N(R^(B1a))₂. Incertain embodiments, at least one instance of R^(B1) is a nitrogenprotecting group when attached to a nitrogen atom. In certainembodiments, at least one instance of R^(B1) is Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to anitrogen atom.

In certain embodiments, at least one instance of R^(B1) is hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted heteroaryl,—OR^(B1a), or —N(R^(B1a))₂, or two instances of R^(B1) are joined toform substituted or unsubstituted heterocyclyl. In certain embodiments,at least one instance of R^(B1) is hydrogen, halogen, or unsubstitutedalkyl. In certain embodiments, at least one instance of R^(B1) ishydrogen, halogen, or unsubstituted C₁₋₆ alkyl. In certain embodiments,at least one instance of R^(B1) is halogen or unsubstituted alkyl. Incertain embodiments, at least one instance of R^(B1) is halogen orunsubstituted C₁₋₆ alkyl.

In compounds of Formula (I), two R^(B1) groups may be joined to formsubstituted or unsubstituted carbocyclyl. In certain embodiments, twoinstances of R^(B1) are joined to form saturated or unsaturatedcarbocyclyl. In certain embodiments, two instances of R^(B1) are joinedto form carbocyclyl including one, two, or three double bonds in thecarbocyclic ring. In certain embodiments, two instances of R^(B1) arejoined to form 3- to 7-membered, monocyclic carbocyclyl. In certainembodiments, two instances of R^(B1) are joined to form 3-memberedcarbocyclyl. In certain embodiments, two instances of R^(B1) are joinedto form 4-membered carbocyclyl. In certain embodiments, two instances ofR^(B1) are joined to form 5-membered carbocyclyl. In certainembodiments, two instances of R^(B1) are joined to form 6-memberedcarbocyclyl. In certain embodiments, two instances of R^(B1) are joinedto form 7-membered carbocyclyl. In certain embodiments, two instances ofR^(B1) are joined to form 5- to 13-membered, bicyclic carbocyclyl.

In certain embodiments, two instances of R^(B1) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(B1) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(B1) are joinedto form heterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, two instances of R^(B1) arejoined to form heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, two instancesof R^(B1) are joined to form 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, two instances of R^(B1) are joined to form

In certain embodiments, two instances of R^(B1) are joined to form

In certain embodiments, two instances of R^(B1) are joined to form

In certain embodiments, two instances of R^(B1) are joined to form

In certain embodiments, two instances of R^(B1) are joined to form 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, two instances of R^(B1) are joined to formsubstituted or unsubstituted aryl. In certain embodiments, two instancesof R^(B1) are joined to form 6- to 14-membered aryl. In certainembodiments, two instances of R^(B1) are joined to form 6- to10-membered aryl. In certain embodiments, two instances of R^(B1) arejoined to form monocyclic aryl. In certain embodiments, two instances ofR^(B1) are joined to form phenyl. In certain embodiments, two instancesof R^(B1) are joined to form bicyclic aryl. In certain embodiments, twoinstances of R^(B1) are joined to form naphthyl.

In certain embodiments, two instances of R^(B1) are joined to formsubstituted or unsubstituted heteroaryl. In certain embodiments, twoinstances of R^(B1) are joined to form monocyclic heteroaryl, whereinone, two, or three atoms in the heteroaryl ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, two instances of R^(B1) are joined to form5-membered, monocyclic heteroaryl. In certain embodiments, two instancesof R^(B1) are joined to form pyrrolyl. In certain embodiments, twoinstances of R^(B1) are joined to form 6-membered, monocyclicheteroaryl. In certain embodiments, two instances of R^(B1) are joinedto form pyridyl. In certain embodiments, two instances of R^(B1) arejoined to form bicyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, twoinstances of R^(B1) are joined to form 9-membered, bicyclic heteroaryl.In certain embodiments, two instances of R^(B1) are joined to form10-membered, bicyclic heteroaryl.

In certain embodiments, at least one instance of R^(B1a) is H. Incertain embodiments, at least one instance of R^(B1a) is substitutedacyl. In certain embodiments, at least one instance of R^(B1a) isunsubstituted acyl. In certain embodiments, at least one instance ofR^(B1a) is acetyl. In certain embodiments, at least one instance ofR^(B1a) is substituted alkyl. In certain embodiments, at least oneinstance of R^(B1a) is unsubstituted alkyl. In certain embodiments, atleast one instance of R^(B1a) is C₁₋₁₂ alkyl. In certain embodiments, atleast one instance of R^(B1a) is C₁₋₆ alkyl. In certain embodiments, atleast one instance of R^(B1a) is methyl. In certain embodiments, atleast one instance of R^(B1a) is ethyl. In certain embodiments, at leastone instance of R^(B1a) is propyl. In certain embodiments, at least oneinstance of R^(B1a) is butyl. In certain embodiments, at least oneinstance of R^(B1a) is pentyl. In certain embodiments, at least oneinstance of R^(B1a) is hexyl. In certain embodiments, at least oneinstance of R^(B1a) is substituted alkenyl. In certain embodiments, atleast one instance of R^(B1a) is unsubstituted alkenyl. In certainembodiments, at least one instance of R^(B1a) is vinyl. In certainembodiments, at least one instance of R^(B1a) is substituted alkynyl. Incertain embodiments, at least one instance of R^(B1a) is unsubstitutedalkynyl. In certain embodiments, at least one instance of R^(B1a) isethynyl. In certain embodiments, at least one instance of R^(B1a) issubstituted carbocyclyl. In certain embodiments, at least one instanceof R^(B1a) is unsubstituted carbocyclyl. In certain embodiments, atleast one instance of R^(B1a) is saturated carbocyclyl. In certainembodiments, at least one instance of R^(B1a) is unsaturatedcarbocyclyl. In certain embodiments, at least one instance of R^(B1a) iscarbocyclyl including one, two, or three double bonds in the carbocyclicring. In certain embodiments, at least one instance of R^(B1a) is 3- to7-membered, monocyclic carbocyclyl. In certain embodiments, at least oneinstance of R^(B1a) is cylcopropyl. In certain embodiments, at least oneinstance of R^(B1a) is cyclobutyl. In certain embodiments, at least oneinstance of R^(B1a) is cyclopentyl. In certain embodiments, at least oneinstance of R^(B1a) is cyclohexyl. In certain embodiments, at least oneinstance of R^(B1a) is cycloheptyl. In certain embodiments, at least oneinstance of R^(B1a) is 5- to 13-membered, bicyclic carbocyclyl. Incertain embodiments, at least one instance of R^(B1a) is substitutedheterocyclyl. In certain embodiments, at least one instance of R^(B1a)is unsubstituted heterocyclyl. In certain embodiments, at least oneinstance of R^(B1a) is saturated heterocyclyl. In certain embodiments,at least one instance of R^(B1a) is unsaturated heterocyclyl. In certainembodiments, at least one instance of R^(B1a) is heterocyclyl includingone, two, or three double bonds in the heterocyclic ring. In certainembodiments, at least one instance of R^(B1a) is heterocyclyl, whereinone, two, or three atoms in the heterocyclic ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, at least one instance of R^(B1a) is 3- to7-membered, monocyclic heterocyclyl. In certain embodiments, at leastone instance of R^(B1a) is 5- to 13-membered, bicyclic heterocyclyl. Incertain embodiments, at least one instance of R^(B1a) is substituted orunsubstituted aryl. In certain embodiments, at least one instance ofR^(B1a) is 6- to 14-membered aryl. In certain embodiments, at least oneinstance of R^(B1a) is 6- to 10-membered aryl. In certain embodiments,at least one instance of R^(B1a) is monocyclic aryl. In certainembodiments, at least one instance of R^(B1a) is phenyl. In certainembodiments, at least one instance of R^(B1a) is bicyclic aryl. Incertain embodiments, at least one instance of R^(B1a) is naphthyl. Incertain embodiments, at least one instance of R^(B1a) is substituted orunsubstituted heteroaryl. In certain embodiments, at least one instanceof R^(B1a) is heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, at least oneinstance of R^(B1a) is monocyclic heteroaryl. In certain embodiments, atleast one instance of R^(B1a) is 5-membered, monocyclic heteroaryl. Incertain embodiments, at least one instance of R^(B1a) is 6-membered,monocyclic heteroaryl. In certain embodiments, at least one instance ofR^(B1a) is pyridyl. In certain embodiments, at least one instance ofR^(B1a) is bicyclic heteroaryl, wherein the point of attachment may beon any atom of the bicyclic heteroaryl ring system, as valency permits.In certain embodiments, at least one instance of R^(B1a) is 9-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(B1a) is 10-membered, bicyclic heteroaryl. In certain embodiments, atleast one instance of R^(B1a) is a nitrogen protecting group whenattached to a nitrogen atom. In certain embodiments, at least oneinstance of R^(B1a) is Bn, Boc, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. Incertain embodiments, R^(B1a) is an oxygen protecting group when attachedto an oxygen atom. In certain embodiments, R^(B1a) is silyl, TBDPS,TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, orbenzoyl when attached to an oxygen atom. In certain embodiments, R^(B1a)is a sulfur protecting group when attached to a sulfur atom. In certainembodiments, R^(B1a) is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to asulfur atom.

In certain embodiments, two instances of R^(B1a) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(B1a) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(B1a) arejoined to form heterocyclyl including one, two, or three double bonds inthe heterocyclic ring. In certain embodiments, two instances of R^(B1a)are joined to form heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, two instancesof R^(B1a) are joined to form 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, two instances of R^(B1a) are joined to form 5-to 13-membered, bicyclic heterocyclyl. In certain embodiments, b is 0.In certain embodiments, b is 1. In certain embodiments, b is 2. Incertain embodiments, b is 3. In certain embodiments, b is 4. In certainembodiments, b is 5.

In certain embodiments, at least one instance of R^(B1) is halogen orsubstituted alkyl; and b is 1. In certain embodiments, at least oneinstance of R^(B1) is halogen or unsubstituted alkyl; and b is 1. Incertain embodiments, at least one instance of R^(B1) is halogen orunsubstituted C₁₋₆ alkyl; and b is 1.

Compounds of Formula (I) include substituent R^(C). In certainembodiments, R^(C) is H. In certain embodiments, R^(C) is substitutedC₁₋₆ alkyl. In certain embodiments, R^(C) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(C) is unsubstituted methyl. In certainembodiments, R^(C) is substituted methyl. In certain embodiments, R^(C)is —CH₂F. In certain embodiments, R^(C) is —CHF₂. In certainembodiments, R^(C) is —CF₃. In certain embodiments, R^(C) is Bn. Incertain embodiments, R^(C) is unsubstituted ethyl. In certainembodiments, R^(C) is substituted ethyl. In certain embodiments, R^(C)is —(CH₂)₂Ph. In certain embodiments, R^(C) is propyl. In certainembodiments, R^(C) is butyl. In certain embodiments, R^(C) is pentyl. Incertain embodiments, R^(C) is hexyl. In certain embodiments, R^(C) is anitrogen protecting group. In certain embodiments, R^(C) is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. In certainembodiments, R^(C) is acetyl.

Compounds of Formula (I) include substituent R^(D). In certainembodiments, R^(D) is H. In certain embodiments, R^(D) is substitutedC₁₋₆ alkyl. In certain embodiments, R^(D) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(D) is unsubstituted methyl. In certainembodiments, R^(D) is substituted methyl. In certain embodiments, R^(D)is —CH₂F. In certain embodiments, R^(D) is —CHF₂. In certainembodiments, R^(D) is —CF₃. In certain embodiments, R^(D) is Bn. Incertain embodiments, R^(D) is unsubstituted ethyl. In certainembodiments, R^(D) is substituted ethyl. In certain embodiments, R^(D)is —(CH₂)₂Ph. In certain embodiments, R^(D) is propyl. In certainembodiments, R^(D) is butyl. In certain embodiments, R^(D) is pentyl. Incertain embodiments, R^(D) is hexyl. In certain embodiments, R^(D) is anitrogen protecting group. In certain embodiments, R^(D) is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

In certain embodiments, each one of R^(C) and R^(D) is hydrogen.

Compounds of Formula (I) may include one or more R^(L) groups. Incertain embodiments, at least one instance of R^(L) is H. In certainembodiments, at least one instance of R^(L) is halogen. In certainembodiments, at least one instance of R^(L) is F. In certainembodiments, at least one instance of R^(L) is Cl. In certainembodiments, at least one instance of R^(L) is Br. In certainembodiments, at least one instance of R^(L) is I (iodine). In certainembodiments, at least one instance of R^(L) is substituted acyl. Incertain embodiments, at least one instance of R^(L) is unsubstitutedacyl. In certain embodiments, at least one instance of R^(L) issubstituted alkyl. In certain embodiments, at least one instance ofR^(L) is unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(L) is C₁₋₁₂ alkyl. In certain embodiments, at least oneinstance of R^(L) is C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(L) is unsubstituted methyl. In certain embodiments, atleast one instance of R^(L) is substituted methyl. In certainembodiments, at least one instance of R^(L) is —CH₂F. In certainembodiments, at least one instance of R^(L) is —CHF₂. In certainembodiments, at least one instance of R^(L) is —CF₃. In certainembodiments, at least one instance of R^(L) is Bn. In certainembodiments, at least one instance of R^(L) is unsubstituted ethyl. Incertain embodiments, at least one instance of R^(L) is substitutedethyl. In certain embodiments, at least one instance of R^(L) is—(CH₂)₂Ph. In certain embodiments, at least one instance of R^(L) ispropyl. In certain embodiments, at least one instance of R^(L) is butyl.In certain embodiments, at least one instance of R^(L) is pentyl. Incertain embodiments, at least one instance of R^(L) is hexyl. In certainembodiments, at least one instance of R^(L) is halogen or substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, at least one instanceof R^(L) is substituted alkenyl. In certain embodiments, at least oneinstance of R^(L) is unsubstituted alkenyl. In certain embodiments, atleast one instance of R^(L) is vinyl. In certain embodiments, at leastone instance of R^(L) is substituted alkynyl. In certain embodiments, atleast one instance of R^(L) is unsubstituted alkynyl. In certainembodiments, at least one instance of R^(L) is ethynyl. In certainembodiments, at least one instance of R^(L) is substituted carbocyclyl.In certain embodiments, at least one instance of R^(L) is unsubstitutedcarbocyclyl. In certain embodiments, at least one instance of R^(L) issaturated carbocyclyl. In certain embodiments, at least one instance ofR_(L) is unsaturated carbocyclyl. In certain embodiments, at least oneinstance of R_(L) is carbocyclyl including one, two, or three doublebonds in the carbocyclic ring. In certain embodiments, at least oneinstance of R_(L) is monocyclic carbocyclyl. In certain embodiments, atleast one instance of R^(L) is 3- to 7-membered, monocyclic carbocyclyl.In certain embodiments, at least one instance of R^(L) is cylcopropyl.In certain embodiments, at least one instance of R^(L) is cyclobutyl. Incertain embodiments, at least one instance of R^(L) is cyclopentyl. Incertain embodiments, at least one instance of R^(L) is cyclohexyl. Incertain embodiments, at least one instance of R^(L) is cycloheptyl. Incertain embodiments, at least one instance of R^(L) is bicycliccarbocyclyl. In certain embodiments, at least one instance of R^(L) is5- to 13-membered, bicyclic carbocyclyl. In certain embodiments, atleast one instance of R^(L) is substituted heterocyclyl. In certainembodiments, at least one instance of R^(L) is unsubstitutedheterocyclyl. In certain embodiments, at least one instance of R^(L) issaturated heterocyclyl. In certain embodiments, at least one instance ofR^(L) is unsaturated heterocyclyl. In certain embodiments, at least oneinstance of R^(L) is heterocyclyl including one, two, or three doublebonds in the heterocyclic ring. In certain embodiments, at least oneinstance of R^(L) is heterocyclyl, wherein one, two, or three atoms inthe heterocyclic ring are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one instance of R^(L) is monocyclic heterocyclyl. In certainembodiments, at least one instance of R^(L) is 3- to 7-membered,monocyclic heterocyclyl. In certain embodiments, at least one instanceof R^(L) is bicyclic heterocyclyl. In certain embodiments, at least oneinstance of R^(L) is 5- to 13-membered, bicyclic heterocyclyl. Incertain embodiments, at least one instance of R^(L) is substituted aryl.In certain embodiments, at least one instance of R^(L) is unsubstitutedaryl. In certain embodiments, at least one instance of R^(L) is 6- to14-membered aryl. In certain embodiments, at least one instance of R^(L)is 6- to 10-membered aryl. In certain embodiments, at least one instanceof R^(L) is substituted phenyl. In certain embodiments, at least oneinstance of R_(L) is unsubstituted phenyl. In certain embodiments, atleast one instance of R^(L) is substituted naphthyl. In certainembodiments, at least one instance of R^(L) is unsubstituted naphthyl.In certain embodiments, at least one instance of R_(L) is substitutedheteroaryl. In certain embodiments, at least one instance of R^(L) isunsubstituted heteroaryl. In certain embodiments, at least one instanceof R^(L) is heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, at least oneinstance of R^(L) is monocyclic heteroaryl. In certain embodiments, atleast one instance of R^(L) is 5-membered, monocyclic heteroaryl. Incertain embodiments, at least one instance of R^(L) is 6-membered,monocyclic heteroaryl. In certain embodiments, at least one instance ofR^(L) is pyridyl. In certain embodiments, at least one instance of R^(L)is bicyclic heteroaryl, wherein the point of attachment may be on anyatom of the bicyclic heteroaryl ring system, as valency permits. Incertain embodiments, at least one instance of R^(L) is 9-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(L) is 10-membered, bicyclic heteroaryl. In certain embodiments, atleast one instance of R^(L) is —OR^(L1). In certain embodiments, atleast one instance of R^(L) is —OMe. In certain embodiments, at leastone instance of R^(L) is —OEt. In certain embodiments, at least oneinstance of R^(L) is —OPr. In certain embodiments, at least one instanceof R^(L) is —OBu. In certain embodiments, at least one instance of R^(L)is —O(pentyl). In certain embodiments, at least one instance of R^(L) is—O(hexyl). In certain embodiments, at least one instance of R^(L) is—OPh. In certain embodiments, at least one instance of R^(L) is —OBn. Incertain embodiments, at least one instance of R^(L) is —O(CH₂)₂Ph. Incertain embodiments, at least one instance of R^(L) is —OH. In certainembodiments, at least one instance of R^(L) is —SR^(L1). In certainembodiments, at least one instance of R^(L) is —SH. In certainembodiments, at least one instance of R^(L) is —N(R^(L1))₂. In certainembodiments, at least one instance of R^(L) is —NH₂. In certainembodiments, at least one instance of R^(L) is —CN. In certainembodiments, at least one instance of R^(L) is —SCN. In certainembodiments, at least one instance of R^(L) is —C(═NR^(L1))R^(L1),—C(═NR^(L1))OR^(L1), or —C(═NR^(L1))N(R^(L1))₂. In certain embodiments,at least one instance of R^(L) is —C(═O)R^(L1), —C(═O)OR^(L1), or—C(═O)N(R^(L1))₂. In certain embodiments, at least one instance of R^(L)is —NO₂. In certain embodiments, at least one instance of R^(L) is—NR^(L1)C(═O)R^(L1), —NR^(L1)C(═O)OR^(L1), or —NR^(L1)C(═O)N(R^(L1))₂.In certain embodiments, at least one instance of R^(L) is —OC(═O)R^(L1),—OC(═O)OR^(L1), or —OC(═O)N(R^(L1))₂.

In certain embodiments, at least one instance of R^(L) is hydrogen,halogen, or unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(L) is hydrogen, halogen, or unsubstituted C₁₋₆ alkyl. Incertain embodiments, at least one instance of R^(L) is halogen orunsubstituted alkyl. In certain embodiments, at least one instance ofR^(L) is halogen or unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(L) is halogen; and l is 1. In certain embodiments, R^(L) isunsubstituted C₁₋₆ alkyl; and l is 1. In certain embodiments, eachinstance of R^(L) is independently halogen or unsubstituted C₁₋₆ alkyl;and l is 2.

In compounds of Formula (I), two R^(L) groups may be joined to formsubstituted or unsubstituted carbocyclyl. In certain embodiments, twoinstances of R^(L) are joined to form saturated or unsaturatedcarbocyclyl. In certain embodiments, two instances of R^(L) are joinedto form carbocyclyl including one, two, or three double bonds in thecarbocyclic ring. In certain embodiments, two instances of R^(L) arejoined to form 3- to 7-membered, monocyclic carbocyclyl. In certainembodiments, two instances of R^(L) are joined to form 3-memberedcarbocyclyl. In certain embodiments, two instances of R^(L) are joinedto form 4-membered carbocyclyl. In certain embodiments, two instances ofR^(L) are joined to form 5-membered carbocyclyl. In certain embodiments,two instances of R^(L) are joined to form 6-membered carbocyclyl. Incertain embodiments, two instances of R^(L) are joined to form7-membered carbocyclyl. In certain embodiments, two instances of R^(L)are joined to form 5- to 13-membered, bicyclic carbocyclyl.

In certain embodiments, two instances of R^(L) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(L) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(L) are joinedto form heterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, two instances of R^(L) arejoined to form heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, two instancesof R^(L) are joined to form 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, two instances of R^(L) are joined to form 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, two instances of R^(L) are joined to formsubstituted or unsubstituted aryl. In certain embodiments, two instancesof R^(L) are joined to form 6- to 14-membered aryl. In certainembodiments, two instances of R^(L) are joined to form 6- to 10-memberedaryl. In certain embodiments, two instances of R^(L) are joined to formmonocyclic aryl. In certain embodiments, two instances of R^(L) arejoined to form phenyl. In certain embodiments, two instances of R^(L)are joined to form bicyclic aryl. In certain embodiments, two instancesof R^(L) are joined to form naphthyl.

In certain embodiments, two instances of R^(L) are joined to formsubstituted or unsubstituted heteroaryl. In certain embodiments, twoinstances of R^(L) are joined to form monocyclic heteroaryl, whereinone, two, or three atoms in the heteroaryl ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, two instances of R^(L) are joined to form5-membered, monocyclic heteroaryl. In certain embodiments, two instancesof R^(L) are joined to form pyrrolyl. In certain embodiments, twoinstances of R^(L) are joined to form 6-membered, monocyclic heteroaryl.In certain embodiments, two instances of R^(L) are joined to formpyridyl. In certain embodiments, two instances of R^(L) are joined toform bicyclic heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, two instances ofR^(L) are joined to form 9-membered, bicyclic heteroaryl. In certainembodiments, two instances of R^(L) are joined to form 10-membered,bicyclic heteroaryl.

In certain embodiments, at least one instance of R^(L1) is H. In certainembodiments, at least one instance of R^(L1) is substituted acyl. Incertain embodiments, at least one instance of R^(L) is unsubstitutedacyl. In certain embodiments, at least one instance of R^(L1) is acetyl.In certain embodiments, at least one instance of R^(L1) is substitutedalkyl. In certain embodiments, at least one instance of R^(L1) isunsubstituted alkyl. In certain embodiments, at least one instance ofR^(L1) is C₁₋₁₂ alkyl. In certain embodiments, at least one instance ofR^(L1) is C₁₋₆ alkyl. In certain embodiments, at least one instance ofR^(L) is methyl. In certain embodiments, at least one instance of R^(L1)is ethyl. In certain embodiments, at least one instance of R^(L) ispropyl. In certain embodiments, at least one instance of R^(L1) isbutyl. In certain embodiments, at least one instance of R^(L1) ispentyl. In certain embodiments, at least one instance of R^(L) is hexyl.In certain embodiments, at least one instance of R^(L1) is substitutedalkenyl. In certain embodiments, at least one instance of R^(L1) isunsubstituted alkenyl. In certain embodiments, at least one instance ofR^(L1) is vinyl. In certain embodiments, at least one instance of R^(L1)is substituted alkynyl. In certain embodiments, at least one instance ofR^(L1) is unsubstituted alkynyl. In certain embodiments, at least oneinstance of R^(L1) is ethynyl. In certain embodiments, at least oneinstance of R^(L1) is substituted carbocyclyl. In certain embodiments,at least one instance of R^(L1) is unsubstituted carbocyclyl. In certainembodiments, at least one instance of R^(L1) is saturated carbocyclyl.In certain embodiments, at least one instance of R^(L1) is unsaturatedcarbocyclyl. In certain embodiments, at least one instance of R^(L1) iscarbocyclyl including one, two, or three double bonds in the carbocyclicring. In certain embodiments, at least one instance of R^(L1) is 3- to7-membered, monocyclic carbocyclyl. In certain embodiments, at least oneinstance of R^(L1) is cylcopropyl. In certain embodiments, at least oneinstance of R^(L1) is cyclobutyl. In certain embodiments, at least oneinstance of R^(L1) is cyclopentyl. In certain embodiments, at least oneinstance of R^(L1) is cyclohexyl. In certain embodiments, at least oneinstance of R^(L1) is cycloheptyl. In certain embodiments, at least oneinstance of R^(L1) is 5- to 13-membered, bicyclic carbocyclyl. Incertain embodiments, at least one instance of R^(L1) is substitutedheterocyclyl. In certain embodiments, at least one instance of R^(L1) isunsubstituted heterocyclyl. In certain embodiments, at least oneinstance of R^(L1) is saturated heterocyclyl. In certain embodiments, atleast one instance of R^(L1) is unsaturated heterocyclyl. In certainembodiments, at least one instance of R^(L1) is heterocyclyl includingone, two, or three double bonds in the heterocyclic ring. In certainembodiments, at least one instance of R^(L1) is heterocyclyl, whereinone, two, or three atoms in the heterocyclic ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, at least one instance of R^(L1) is 3- to7-membered, monocyclic heterocyclyl. In certain embodiments, at leastone instance of R^(L1) is 5- to 13-membered, bicyclic heterocyclyl. Incertain embodiments, at least one instance of R^(L1) is substituted orunsubstituted aryl. In certain embodiments, at least one instance ofR^(L1) is 6- to 14-membered aryl. In certain embodiments, at least oneinstance of R^(L1) is 6- to 10-membered aryl. In certain embodiments, atleast one instance of R^(L1) is monocyclic aryl. In certain embodiments,at least one instance of R^(L1) is phenyl. In certain embodiments, atleast one instance of R^(L1) is bicyclic aryl. In certain embodiments,at least one instance of R^(L1) is naphthyl. In certain embodiments, atleast one instance of R^(L1) is substituted or unsubstituted heteroaryl.In certain embodiments, at least one instance of R^(L1) is heteroaryl,wherein one, two, three, or four atoms in the heteroaryl ring areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, at least one instance of R^(L1) ismonocyclic heteroaryl. In certain embodiments, at least one instance ofR^(L1) is 5-membered, monocyclic heteroaryl. In certain embodiments, atleast one instance of R^(L1) is 6-membered, monocyclic heteroaryl. Incertain embodiments, at least one instance of R^(L1) is pyridyl. Incertain embodiments, at least one instance of R^(L1) is bicyclicheteroaryl, wherein the point of attachment may be on any atom of thebicyclic heteroaryl ring system, as valency permits. In certainembodiments, at least one instance of R^(L1) is 9-membered, bicyclicheteroaryl. In certain embodiments, at least one instance of R^(L1) is10-membered, bicyclic heteroaryl. In certain embodiments, at least oneinstance of R^(L1) is a nitrogen protecting group when attached to anitrogen atom. In certain embodiments, at least one instance of R^(L1)is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Tswhen attached to a nitrogen atom. In certain embodiments, R^(L1) is anoxygen protecting group when attached to an oxygen atom. In certainembodiments, R^(L1) is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP,t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygenatom. In certain embodiments, R^(L1) is a sulfur protecting group whenattached to a sulfur atom. In certain embodiments, R^(L1) isacetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl,or triphenylmethyl when attached to a sulfur atom.

In certain embodiments, two instances of R^(L1) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(L1) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(L1) are joinedto form heterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, two instances of R^(L1) arejoined to form heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, two instancesof R^(L1) are joined to form 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, two instances of R^(L1) are joined to form 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, l is 0. In certain embodiments, l is 1. Incertain embodiments, l is 2. In certain embodiments, l is 3. In certainembodiments, l is 4.

In compounds of Formula (I), the X and Y moieties may be directlyconnected to each other, or there may be one or more methylene groupsbetween X and Y. In certain embodiments, m is 0. In certain embodiments,m is 1, 2, 3, 4, or 5. In certain embodiments, m is 1. In certainembodiments, m is 2. In certain embodiments, m is 3. In certainembodiments, m is 4. In certain embodiments, m is 5.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof

In certain embodiments, the compound is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

The present invention also provides compounds of Formula (II):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof;wherein:

U is a bond, C(═O), —S(═O)—, —S(═O)₂—, —N(R^(N))—S(═O)—, or—N(R^(N))—S(═O)₂—;

V is a bond, CH, CH₂, —C(═O)—, —S(═O)—, or —S(═O)₂—;

W is a bond, CH₂, —S(═O)₂—, —S(═O)₂—N(R^(K))—, or

wherein when V is CH and W is CH₂, V and R^(G) are joined to formsubstituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl;

Ring Z is substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

R^(N) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

R^(K) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

R^(E) is substituted or unsubstituted alkyl or of the formula:

Ring E is substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

each instance of R^(E1) is independently hydrogen, halogen, substitutedor unsubstituted acyl, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(E1a), —N(R^(E1a))₂, —SR^(E1a), —CN, —SCN,—C(═NR^(E1a))R^(E1a), —C(═NR^(E1a))OR^(E1a), —C(═NR^(E1a))N(R^(E1a))₂,—C(═O)R^(E1a), —C(═O)OR^(E1a), —C(═O)N(R^(E1a))₂, —NO₂,—NR^(E1a)C(═O)R^(E1a), —NR^(E1a)C(═O)OR^(E1a),—NR^(E1a)C(═O)N(R^(E1a))₂, —OC(═O)R^(E1a), —OC(═O)OR^(E1a), or—OC(═O)N(R^(E1a))₂, or two instances of R^(E1) are joined to formsubstituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

each instance of R^(E1a) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(E1a) are joined to form substituted or unsubstituted heterocyclyl;

e is 0, 1, 2, 3, 4, or 5;

R^(F) is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heterocyclyl, or a nitrogen protecting group, or R^(F) andR^(G) are joined to form a substituted or unsubstituted heterocyclicring of the formula:

Ring F is substituted or unsubstituted, 4- to 7-membered, monocyclicheterocyclyl, or substituted or unsubstituted, 7- to 10-membered, spirobicyclic heterocyclyl, wherein one or two atoms in the heterocyclic ringare independently selected from the group consisting of oxygen andnitrogen;

each instance of R^(F1) is independently hydrogen, halogen, substitutedor unsubstituted alkyl, —OR^(F1a), —N(R^(F1a))₂, oxo, or a nitrogenprotecting group when attached to a nitrogen atom;

each instance of R^(F1a) is independently hydrogen, substituted orunsubstituted alkyl, or a nitrogen protecting group when attached to anitrogen atom, or an oxygen protecting group when attached to an oxygenatom, or two instances of R^(F1a) are joined to form substituted orunsubstituted heterocyclyl;

f is 0, 1, 2, or 3;

R^(G) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group, or R^(G) and R^(F) are joined to formsubstituted or unsubstituted heterocyclyl;

R^(H) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

R^(J) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group;

each instance of R^(M) is independently hydrogen, halogen, substitutedor unsubstituted acyl, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(M1), —N(R^(M1))₂, —SR^(M1), —CN, —SCN,—C(═NR^(M1))R^(M1), —C(═NR^(M1))OR^(M1), —C(═NR^(M1))N(R^(M1))₂,—C(═O)R^(M1), —C(═O)OR^(M1), —C(═O)N(R^(M1))₂, —NO₂,—NR^(M1)C(═O)R^(M1), —NR^(M1)C(═O)OR^(M1), —NR^(M1)C(═O)N(R^(M1))₂,—OC(═O)R^(M1), —OC(═O)OR^(M1), or —OC(═O)N(R^(M1))₂, or two instances ofR^(M) are joined to form substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl;

each instance of R^(M1) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(M1) are joined to form substituted or unsubstituted heterocyclyl;

-   -   p is 0, 1, 2, 3, or 4; and    -   n is 0, 1, 2, 3, 4, or 5.

Compounds of Formula (II) include moiety U. In certain embodiments, U isa bond. In certain embodiments, U is a single bond. In certainembodiments, U is —C(═O)—. In certain embodiments, U is —S(═O)—. Incertain embodiments, U is —S(═O)₂—. In certain embodiments, U is—N(R^(N))—S(═O)—. In certain embodiments, U is —NH—S(═O)—. In certainembodiments, U is —N(R^(N))—S(═O)₂—. In certain embodiments, U is—NH—S(═O)₂—.

Compounds of Formula (II) include moiety V. In certain embodiments, V isa bond. In certain embodiments, V is a single bond. In certainembodiments, V is CH. In certain embodiments, V is CH₂. In certainembodiments, V is —C(═O)—. In certain embodiments, V is —S(═O)—. Incertain embodiments, V is —S(═O)₂—.

In certain embodiments, each one of U and V is a bond. In certainembodiments, U is a bond; and V is —C(═O)—, —S(═O)—, or —S(═O)₂—. Incertain embodiments, U is —C(═O)—, —S(═O)—, or —S(═O)₂—; and V is abond. In certain embodiments, each one of U and V is independently—C(═O)—, —S(═O)—, or —S(═O)₂—. In certain embodiments, U is a bond; andV is —C(═O)—. In certain embodiments, U is —C(═O)—; and V is a bond. Incertain embodiments, each one of U and V is —C(═O)—.

Compounds of Formula (II) include moiety W. In certain embodiments, W isa bond. In certain embodiments, W is a single bond. In certainembodiments, W is CH₂. In certain embodiments, W is ═CH—. In certainembodiments, W is —CH═. In certain embodiments, W is —S(═O)₂—. Incertain embodiments, W is —S(═O)₂—N(R^(K))—. In certain embodiments, Wis —S(═O)₂—NH—. In certain embodiments, W is of the formula:

In certain embodiments, W is of the formula:

In certain embodiments, V is CH; W is CH₂; and V and R^(G) are joined toform substituted or unsubstituted, 5- to 6-membered, monocyclicheteroaryl. In certain embodiments, V is CH; W is CH₂; and V and R^(G)are joined to form substituted or unsubstituted, 5- to 6-membered,monocyclic heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, V is CH; W is CH₂;and V and R^(G) are joined to form substituted pyrazolyl. In certainembodiments, V is CH; W is CH₂; and V and R^(G) are joined to formunsubstituted pyrazolyl. In certain embodiments, V is CH; W is CH₂; Vand R^(G) are joined to form substituted or unsubstituted, 5- to6-membered, monocyclic heteroaryl; U is a bond; and n is 0. In certainembodiments, V is CH; W is CH₂; V and R^(G) are joined to formsubstituted or unsubstituted pyrazolyl; U is a bond; and n is 0.

In certain embodiments, R^(N) is H. In certain embodiments, R^(N) issubstituted C₁₋₆ alkyl. In certain embodiments, R^(N) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(N) is unsubstituted methyl. Incertain embodiments, R^(N) is substituted methyl. In certainembodiments, R^(N) is —CH₂F. In certain embodiments, R^(N) is —CHF₂. Incertain embodiments, R^(N) is —CF₃. In certain embodiments, R^(N) is Bn.In certain embodiments, R^(N) is unsubstituted ethyl. In certainembodiments, R^(N) is substituted ethyl. In certain embodiments, R^(N)is —(CH₂)₂Ph. In certain embodiments, R^(N) is propyl. In certainembodiments, R^(N) is butyl. In certain embodiments, R^(N) is pentyl. Incertain embodiments, R^(N) is hexyl. In certain embodiments, R^(N) is anitrogen protecting group. In certain embodiments, R^(N) is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

In certain embodiments, R^(K) is H. In certain embodiments, R^(K) issubstituted C₁₋₆ alkyl. In certain embodiments, R^(K) is unsubstitutedC₁₋₆ alkyl. In certain embodiments, R^(K) is unsubstituted methyl. Incertain embodiments, R^(K) is substituted methyl. In certainembodiments, R^(K) is —CH₂F. In certain embodiments, R^(K) is —CHF₂. Incertain embodiments, R^(K) is —CF₃. In certain embodiments, R^(K) is Bn.In certain embodiments, R^(K) is unsubstituted ethyl. In certainembodiments, R^(K) is substituted ethyl. In certain embodiments, R^(K)is —(CH₂)₂Ph. In certain embodiments, R^(K) is propyl. In certainembodiments, R^(K) is butyl. In certain embodiments, R^(K) is pentyl. Incertain embodiments, R^(K) is hexyl. In certain embodiments, R^(K) is anitrogen protecting group. In certain embodiments, R^(K) is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

Compounds of Formula (II) include Ring Z. In certain embodiments, Ring Zis substituted carbocyclyl. In certain embodiments, Ring Z isunsubstituted carbocyclyl. In certain embodiments, Ring Z is saturatedcarbocyclyl. In certain embodiments, Ring Z is unsaturated carbocyclyl.In certain embodiments, Ring Z is carbocyclyl including one, two, orthree double bonds in the carbocyclic ring. In certain embodiments, RingZ is monocyclic carbocyclyl. In certain embodiments, Ring Z is 3- to7-membered, monocyclic carbocyclyl. In certain embodiments, Ring Z issubstituted cylcopropyl. In certain embodiments, Ring Z is unsubstitutedcylcopropyl. In certain embodiments, Ring Z is cyclobutyl. In certainembodiments, Ring Z is cyclopentyl. In certain embodiments, Ring Z iscyclohexyl. In certain embodiments, Ring Z is cycloheptyl. In certainembodiments, Ring Z is bicyclic carbocyclyl. In certain embodiments,Ring Z is 5- to 13-membered, bicyclic carbocyclyl.

In certain embodiments, Ring Z is substituted heterocyclyl. In certainembodiments, Ring Z is unsubstituted heterocyclyl. In certainembodiments, Ring Z is saturated heterocyclyl. In certain embodiments,Ring Z is unsaturated heterocyclyl. In certain embodiments, Ring Z isheterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, Ring Z is heterocyclyl,wherein one, two, or three atoms in the heterocyclic ring areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, Ring Z is monocyclic heterocyclyl.In certain embodiments, Ring Z is 3- to 7-membered, monocyclicheterocyclyl. In certain embodiments, Ring Z is 5-membered, monocyclicheterocyclyl. In certain embodiments, Ring Z is substituted orunsubstituted tetrahydrofuranyl. In certain embodiments, Ring Z is6-membered, monocyclic heterocyclyl. In certain embodiments, Ring Z issubstituted or unsubstituted tetrahydropyranyl. In certain embodiments,Ring Z is bicyclic heterocyclyl. In certain embodiments, Ring Z is 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, Ring Z is substituted aryl. In certainembodiments, Ring Z is unsubstituted aryl. In certain embodiments, RingZ is 6- to 14-membered aryl. In certain embodiments, Ring Z is 6- to10-membered aryl. In certain embodiments, Ring Z is unsubstitutedphenyl. In certain embodiments, Ring Z is substituted phenyl. In certainembodiments, Ring Z is of the formula:

In certain embodiments, Ring Z is of the formula:

In certain embodiments, Ring Z is of the formula:

In certain embodiments, Ring Z is substituted heteroaryl. In certainembodiments, Ring Z is unsubstituted heteroaryl. In certain embodiments,Ring Z is 5- to 6-membered, monocyclic heteroaryl, wherein one, two,three, or four atoms in the heteroaryl ring are independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, Ring Z is 5-membered, monocyclic heteroaryl. In certainembodiments, Ring Z is 5-membered, monocyclic heteroaryl, wherein one ofthe five atoms in the heteroaryl ring is nitrogen, oxygen, or sulfur.

Compounds of Formula (II) include substituent R^(E). In certainembodiments, R^(E) is substituted alkyl. In certain embodiments, R^(E)is unsubstituted alkyl. In certain embodiments, R^(E) is substitutedC₁₋₆ alkyl. In certain embodiments, R^(E) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(E) is unsubstituted methyl. In certainembodiments, R^(E) is substituted methyl. In certain embodiments, R^(E)is —CH₂F. In certain embodiments, R^(E) is —CHF₂. In certainembodiments, R^(E) is —CF₃. In certain embodiments, R^(E) is Bn. Incertain embodiments, R^(E) is unsubstituted ethyl. In certainembodiments, R^(E) is substituted ethyl. In certain embodiments, R^(E)is —(CH₂)₂Ph. In certain embodiments, R^(E) is propyl. In certainembodiments, R^(E) is butyl. In certain embodiments, R^(E) isunsubstituted t-butyl. In certain embodiments, R^(E) is pentyl. Incertain embodiments, R^(E) is hexyl.

In certain embodiments, R^(E) is of the formula:

In certain embodiments, Ring E is substituted carbocyclyl. In certainembodiments, Ring E is unsubstituted carbocyclyl. In certainembodiments, Ring E is saturated carbocyclyl. In certain embodiments,Ring E is unsaturated carbocyclyl. In certain embodiments, Ring E iscarbocyclyl including one, two, or three double bonds in the carbocyclicring. In certain embodiments, Ring E is monocyclic carbocyclyl. Incertain embodiments, Ring E is 3- to 7-membered, monocyclic carbocyclyl.In certain embodiments, Ring E is substituted cylcopropyl. In certainembodiments, Ring E is unsubstituted cylcopropyl. In certainembodiments, Ring E is cyclobutyl. In certain embodiments, Ring E iscyclopentyl. In certain embodiments, Ring E is cyclohexyl. In certainembodiments, Ring E is cycloheptyl. In certain embodiments, Ring E isbicyclic carbocyclyl. In certain embodiments, Ring E is 5- to13-membered, bicyclic carbocyclyl.

In certain embodiments, Ring E is substituted heterocyclyl. In certainembodiments, Ring E is unsubstituted heterocyclyl. In certainembodiments, Ring E is saturated heterocyclyl. In certain embodiments,Ring E is unsaturated heterocyclyl. In certain embodiments, Ring E isheterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, Ring E is heterocyclyl,wherein one, two, or three atoms in the heterocyclic ring areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, Ring E is monocyclic heterocyclyl.In certain embodiments, Ring E is 3- to 7-membered, monocyclicheterocyclyl. In certain embodiments, Ring E is 5-membered, monocyclicheterocyclyl. In certain embodiments, Ring E is substituted orunsubstituted tetrahydrofuranyl. In certain embodiments, Ring E is6-membered, monocyclic heterocyclyl. In certain embodiments, Ring E issubstituted or unsubstituted tetrahydropyranyl. In certain embodiments,Ring E is bicyclic heterocyclyl. In certain embodiments, Ring E is 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, Ring E is substituted aryl. In certainembodiments, Ring E is unsubstituted aryl. In certain embodiments, RingE is 6- to 14-membered aryl. In certain embodiments, Ring E is 6- to10-membered aryl. In certain embodiments, Ring E is unsubstitutedphenyl. In certain embodiments, Ring E is substituted phenyl. In certainembodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is substituted naphthyl. In certainembodiments, Ring E is unsubstituted naphthyl.

In certain embodiments, Ring E is substituted heteroaryl. In certainembodiments, Ring E is unsubstituted heteroaryl. In certain embodiments,Ring E is 5- to 6-membered, monocyclic heteroaryl, wherein one, two,three, or four atoms in the heteroaryl ring are independently selectedfrom the group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, Ring E is 5-membered, monocyclic heteroaryl. In certainembodiments, Ring E is 5-membered, monocyclic heteroaryl, wherein one ofthe five atoms in the heteroaryl ring is nitrogen, oxygen, or sulfur. Incertain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is 5-membered, monocyclic heteroaryl,wherein two of the five atoms in the heteroaryl ring are independentlynitrogen, oxygen, or sulfur. In certain embodiments, Ring E is of theformula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is 5-membered, monocyclic heteroaryl,wherein three of the five atoms in the heteroaryl ring are independentlynitrogen, oxygen, or sulfur. In certain embodiments, Ring E is of theformula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is 5-membered, monocyclic heteroaryl,wherein only four of the five atoms in the heteroaryl ring are nitrogen,oxygen, or sulfur. In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is 6-membered, monocyclic heteroaryl,wherein one, two, or three atoms in the heteroaryl ring is nitrogen. Incertain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is of the formula:

In certain embodiments, Ring E is bicyclic heteroaryl, wherein the pointof attachment may be on any atom of the bicyclic heteroaryl ring system,as valency permits. In certain embodiments, Ring E is substitutedbicyclic heteroaryl. In certain embodiments, Ring E is unsubstitutedbicyclic heteroaryl. In certain embodiments, Ring E is 9- or10-membered, bicyclic heteroaryl, wherein one, two, three, or four atomsin the bicyclic ring of the heteroaryl are independently selected fromthe group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, Ring E is 8- to 10-membered, bicyclic heteroaryl, whereinone atom in the bicyclic ring of the heteroaryl is nitrogen, oxygen, orsulfur. In certain embodiments, Ring E is 8- to 10-membered, bicyclicheteroaryl, wherein two atoms in the bicyclic ring of the heteroaryl areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, Ring E is 8- to 10-membered,bicyclic heteroaryl, wherein three atoms in the bicyclic ring of theheteroaryl are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, Ring E is 8- to10-membered, bicyclic heteroaryl, wherein only four atoms in thebicyclic ring of the heteroaryl are independently selected from thegroup consisting of nitrogen, oxygen, and sulfur.

In certain embodiments, R^(E) is t-butyl. In certain embodiments, R^(E)is cyclopropyl. In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

In certain embodiments, R^(E) is of the formula:

When R^(E) is of the formula:

compounds of Formula (II) may include one or more substituents R^(E1).In certain embodiments, at least one instance of R^(E1) is H. In certainembodiments, at least one instance of R^(E1) is halogen. In certainembodiments, at least one instance of R^(E1) is F. In certainembodiments, at least one instance of R^(E1) is Cl. In certainembodiments, at least one instance of R^(E1) is Br. In certainembodiments, at least one instance of R^(E1) is I (iodine). In certainembodiments, at least one instance of R^(E1) is substituted acyl. Incertain embodiments, at least one instance of R^(E1) is unsubstitutedacyl. In certain embodiments, at least one instance of R^(E1) issubstituted alkyl. In certain embodiments, at least one instance ofR^(E1) is unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(E1) is C₁₋₁₂ alkyl. In certain embodiments, at least oneinstance of R^(E1) is C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(E1) is unsubstituted methyl. In certain embodiments, atleast one instance of R^(E1) is substituted methyl. In certainembodiments, at least one instance of R^(E1) is —CH₂F. In certainembodiments, at least one instance of R^(E1) is —CHF₂. In certainembodiments, at least one instance of R^(E1) is —CF₃. In certainembodiments, at least one instance of R^(E1) is —CH₂—N(R^(E1a))₂. Incertain embodiments, at least one instance of R^(E1) is—CH₂—N(unsubstituted C₁₋₆ alkyl)-(CH₂)₂₋₄—OH. In certain embodiments, atleast one instance of R^(E1) is —CH₂—N(CH₃)—(CH₂)₂—OH. In certainembodiments, at least one instance of R^(E1) is of the formula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is—CH₂—NH(R^(E1a)). In certain embodiments, at least one instance ofR^(E1) is —CH₂—NH(unsubstituted C₁₋₆ alkyl). In certain embodiments, atleast one instance of R^(E1) is —CH₂—NH(CH₃). In certain embodiments, atleast one instance of R^(E1) is Bn. In certain embodiments, at least oneinstance of R^(E1) is unsubstituted ethyl. In certain embodiments, atleast one instance of R^(E1) is substituted ethyl. In certainembodiments, at least one instance of R^(E1) is —(CH₂)₂Ph. In certainembodiments, at least one instance of R^(E1) is propyl. In certainembodiments, at least one instance of R^(E1) is butyl. In certainembodiments, at least one instance of R^(E1) is pentyl. In certainembodiments, at least one instance of R^(E1) is hexyl. In certainembodiments, at least one instance of R^(E1) is halogen or substitutedor unsubstituted C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(E1) is substituted alkenyl. In certain embodiments, atleast one instance of R^(E1) is unsubstituted alkenyl. In certainembodiments, at least one instance of R^(E1) is vinyl. In certainembodiments, at least one instance of R^(E1) is substituted alkynyl. Incertain embodiments, at least one instance of R^(E1) is unsubstitutedalkynyl. In certain embodiments, at least one instance of R^(E1) isethynyl. In certain embodiments, at least one instance of R^(E1) issubstituted carbocyclyl. In certain embodiments, at least one instanceof R^(E1) is unsubstituted carbocyclyl. In certain embodiments, at leastone instance of R^(E1) is saturated carbocyclyl. In certain embodiments,at least one instance of R^(E1) is unsaturated carbocyclyl. In certainembodiments, at least one instance of R^(E1) is carbocyclyl includingone, two, or three double bonds in the carbocyclic ring. In certainembodiments, at least one instance of R^(E1) is monocyclic carbocyclyl.In certain embodiments, at least one instance of R^(E1) is 3- to7-membered, monocyclic carbocyclyl. In certain embodiments, at least oneinstance of R^(E1) is cylcopropyl. In certain embodiments, at least oneinstance of R^(E1) is cyclobutyl. In certain embodiments, at least oneinstance of R^(E1) is cyclopentyl. In certain embodiments, at least oneinstance of R^(E1) is cyclohexyl. In certain embodiments, at least oneinstance of R^(E1) is cycloheptyl. In certain embodiments, at least oneinstance of R^(E1) is bicyclic carbocyclyl. In certain embodiments, atleast one instance of R^(E1) is 5- to 13-membered, bicyclic carbocyclyl.In certain embodiments, at least one instance of R^(E1) is substitutedheterocyclyl. In certain embodiments, at least one instance of R^(E1) isunsubstituted heterocyclyl. In certain embodiments, at least oneinstance of R^(E1) is saturated heterocyclyl. In certain embodiments, atleast one instance of R^(E1) is unsaturated heterocyclyl. In certainembodiments, at least one instance of R^(E1) is heterocyclyl includingone, two, or three double bonds in the heterocyclic ring. In certainembodiments, at least one instance of R^(E1) is heterocyclyl, whereinone, two, or three atoms in the heterocyclic ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, at least one instance of R^(E1) is monocyclicheterocyclyl. In certain embodiments, at least one instance of R^(E1) is3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, atleast one instance of R^(E1) is of the formula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is bicyclicheterocyclyl. In certain embodiments, at least one instance of R^(E1) is5- to 13-membered, bicyclic heterocyclyl. In certain embodiments, atleast one instance of R^(E1) is substituted aryl. In certainembodiments, at least one instance of R^(E1) is unsubstituted aryl. Incertain embodiments, at least one instance of R^(E1) is 6- to14-membered aryl. In certain embodiments, at least one instance ofR^(E1) is 6- to 10-membered aryl. In certain embodiments, at least oneinstance of R^(E1) is substituted phenyl. In certain embodiments, atleast one instance of R^(E1) is unsubstituted phenyl. In certainembodiments, at least one instance of R^(E1) is substituted naphthyl. Incertain embodiments, at least one instance of R^(E1) is unsubstitutednaphthyl. In certain embodiments, at least one instance of R^(E1) issubstituted heteroaryl. In certain embodiments, at least one instance ofR^(E1) is unsubstituted heteroaryl. In certain embodiments, at least oneinstance of R^(E1) is heteroaryl, wherein one, two, three, or four atomsin the heteroaryl ring are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one instance of R^(E1) is monocyclic heteroaryl. In certainembodiments, at least one instance of R^(E1) is 5-membered, monocyclicheteroaryl. In certain embodiments, at least one instance of R^(E1) isof the formula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is 6-membered,monocyclic heteroaryl. In certain embodiments, at least one instance ofR^(E1) is pyridyl. In certain embodiments, at least one instance ofR^(E1) is bicyclic heteroaryl, wherein the point of attachment may be onany atom of the bicyclic heteroaryl ring system, as valency permits. Incertain embodiments, at least one instance of R^(E1) is 9-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(E1) is of the formula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is 10-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(E1) is —OR^(E1a). In certain embodiments, at least one instance ofR^(E1) is —OMe. In certain embodiments, at least one instance of R^(E1)is —OEt. In certain embodiments, at least one instance of R^(E1) is—OPr. In certain embodiments, at least one instance of R^(E1) is —OBu.In certain embodiments, at least one instance of R^(E1) is —O(pentyl).In certain embodiments, at least one instance of R^(E1) is —O(hexyl). Incertain embodiments, at least one instance of R^(E1) is —OPh. In certainembodiments, at least one instance of R^(E1) is —OBn. In certainembodiments, at least one instance of R^(E1) is —O(CH₂)₂Ph. In certainembodiments, at least one instance of R^(E1) is —OH. In certainembodiments, at least one instance of R^(E1) is —O—CF₃. In certainembodiments, at least one instance of R^(E1) is —O—(CH₂)₂₋₄—N(R^(E1a))₂.In certain embodiments, at least one instance of R^(E1) is—O—(CH₂)₂₋₄—N(unsubstituted C₁₋₆ alkyl)₂. In certain embodiments, atleast one instance of R^(E1) is —O—(CH₂)₂—N(CH₃)₂. In certainembodiments, at least one instance of R^(E1) is —O—(CH₂)₃—N(CH₃)₂. Incertain embodiments, at least one instance of R^(E1) is of the formula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is of theformula:

In certain embodiments, at least one instance of R^(E1) is —SR^(E1a). Incertain embodiments, at least one instance of R^(E1) is —SH. In certainembodiments, at least one instance of R^(E1) is —N(R^(E1a))₂. In certainembodiments, at least one instance of R^(E1) is —NH₂. In certainembodiments, at least one instance of R^(E1) is —CN. In certainembodiments, at least one instance of R^(E1) is —SCN. In certainembodiments, at least one instance of R^(E1) is —C(═NR^(E1a))R^(E1a),—C(═NR^(E1a))OR^(E1a), or —C(═NR^(E1a))N(R^(E1a))₂. In certainembodiments, at least one instance of R^(E1) is —C(═O)R^(E1a),C(═O)OR^(E1a), or —C(═O)N(R^(E1a))₂. In certain embodiments, at leastone instance of R^(E1) is —NO₂. In certain embodiments, at least oneinstance of R^(E1) is —NR^(E1a)C(═O)R^(E1a), —NR^(E1a)C(═O)OR^(E1a), or—NR^(E1a)C(═O)N(R^(E1a))₂. In certain embodiments, at least one instanceof R^(E1) is —OC(═O)R^(E1a), —OC(═O)OR^(E1a), or —OC(═O)N(R^(E1a))₂.

In certain embodiments, at least one instance of R^(E1) is hydrogen,halogen, or unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(E1) is hydrogen, halogen, or unsubstituted C₁₋₆ alkyl. Incertain embodiments, at least one instance of R^(E1) is halogen orunsubstituted alkyl. In certain embodiments, at least one instance ofR^(E1) is halogen or unsubstituted C₁₋₆ alkyl.

In compounds of Formula (II), two R^(E1) groups may be joined to formsubstituted or unsubstituted carbocyclyl. In certain embodiments, twoinstances of R^(E1) are joined to form saturated or unsaturatedcarbocyclyl. In certain embodiments, two instances of R^(E1) are joinedto form carbocyclyl including one, two, or three double bonds in thecarbocyclic ring. In certain embodiments, two instances of R^(E1) arejoined to form 3- to 7-membered, monocyclic carbocyclyl. In certainembodiments, two instances of R^(E1) are joined to form 3-memberedcarbocyclyl. In certain embodiments, two instances of R^(E1) are joinedto form 4-membered carbocyclyl. In certain embodiments, two instances ofR^(E1) are joined to form 5-membered carbocyclyl. In certainembodiments, two instances of R^(E1) are joined to form 6-memberedcarbocyclyl. In certain embodiments, two instances of R^(E1) are joinedto form 7-membered carbocyclyl. In certain embodiments, two instances ofR^(E1) are joined to form 5- to 13-membered, bicyclic carbocyclyl.

In certain embodiments, two instances of R^(E1) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(E1) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(E1) are joinedto form heterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, two instances of R^(E1) arejoined to form heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, two instancesof R^(E1) are joined to form 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, two instances of R^(E1) are joined to form

In certain embodiments, two instances of R^(E1) are joined to form

In certain embodiments, two instances of R^(E1) are joined to form

In certain embodiments, two instances of R^(E1) are joined to form

In certain embodiments, two instances of R^(E1) are joined to form 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, two instances of R^(E1) are joined to formsubstituted or unsubstituted aryl. In certain embodiments, two instancesof R^(E1) are joined to form 6- to 14-membered aryl. In certainembodiments, two instances of R^(E1) are joined to form 6- to10-membered aryl. In certain embodiments, two instances of R^(E1) arejoined to form monocyclic aryl. In certain embodiments, two instances ofR^(E1) are joined to form phenyl. In certain embodiments, two instancesof R^(E1) are joined to form bicyclic aryl. In certain embodiments, twoinstances of R^(E1) are joined to form naphthyl.

In certain embodiments, two instances of R^(E1) are joined to formsubstituted or unsubstituted heteroaryl. In certain embodiments, twoinstances of R^(E1) are joined to form monocyclic heteroaryl, whereinone, two, or three atoms in the heteroaryl ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, two instances of R^(E1) are joined to form5-membered, monocyclic heteroaryl. In certain embodiments, two instancesof R^(E1) are joined to form pyrrolyl. In certain embodiments, twoinstances of R^(E1) are joined to form 6-membered, monocyclicheteroaryl. In certain embodiments, two instances of R^(E1) are joinedto form pyridyl. In certain embodiments, two instances of R^(E1) arejoined to form bicyclic heteroaryl, wherein one, two, three, or fouratoms in the heteroaryl ring are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, twoinstances of R^(E) are joined to form 9-membered, bicyclic heteroaryl.In certain embodiments, two instances of R^(E1) are joined to form10-membered, bicyclic heteroaryl.

In certain embodiments, at least one instance of R^(E1a) is H. Incertain embodiments, at least one instance of R^(E1a) is substitutedacyl. In certain embodiments, at least one instance of R^(E1a) isunsubstituted acyl. In certain embodiments, at least one instance ofR^(E1a) is acetyl. In certain embodiments, at least one instance ofR^(E1a) is substituted alkyl. In certain embodiments, at least oneinstance of R^(E1a) is unsubstituted alkyl. In certain embodiments, atleast one instance of R^(E1a) is C₁₋₁₂ alkyl. In certain embodiments, atleast one instance of R^(E1a) is C₁₋₆ alkyl. In certain embodiments, atleast one instance of R^(E1a) is methyl. In certain embodiments, atleast one instance of R^(E1a) is ethyl. In certain embodiments, at leastone instance of R^(E1a) is propyl. In certain embodiments, at least oneinstance of R^(E1a) is butyl. In certain embodiments, at least oneinstance of R^(E1a) is pentyl. In certain embodiments, at least oneinstance of R^(E1a) is hexyl. In certain embodiments, at least oneinstance of R^(E1a) is substituted alkenyl. In certain embodiments, atleast one instance of R^(E1a) is unsubstituted alkenyl. In certainembodiments, at least one instance of R^(E1a) is vinyl. In certainembodiments, at least one instance of R^(E1a) is substituted alkynyl. Incertain embodiments, at least one instance of R^(E1a) is unsubstitutedalkynyl. In certain embodiments, at least one instance of R^(E1a) isethynyl. In certain embodiments, at least one instance of R^(E1a) issubstituted carbocyclyl. In certain embodiments, at least one instanceof R^(E1a) is unsubstituted carbocyclyl. In certain embodiments, atleast one instance of R^(E1a) is saturated carbocyclyl. In certainembodiments, at least one instance of R^(E1a) is unsaturatedcarbocyclyl. In certain embodiments, at least one instance of R^(E1a) iscarbocyclyl including one, two, or three double bonds in the carbocyclicring. In certain embodiments, at least one instance of R^(E1a) is 3- to7-membered, monocyclic carbocyclyl. In certain embodiments, at least oneinstance of R^(E1a) is cylcopropyl. In certain embodiments, at least oneinstance of R^(E1a) is cyclobutyl. In certain embodiments, at least oneinstance of R^(E1a) is cyclopentyl. In certain embodiments, at least oneinstance of R^(E1a) is cyclohexyl. In certain embodiments, at least oneinstance of R^(E1a) is cycloheptyl. In certain embodiments, at least oneinstance of R^(E1a) is 5- to 13-membered, bicyclic carbocyclyl. Incertain embodiments, at least one instance of R^(E1a) is substitutedheterocyclyl. In certain embodiments, at least one instance of R^(E1a)is unsubstituted heterocyclyl. In certain embodiments, at least oneinstance of R^(E1a) is saturated heterocyclyl. In certain embodiments,at least one instance of R^(E1a) is unsaturated heterocyclyl. In certainembodiments, at least one instance of R^(E1a) is heterocyclyl includingone, two, or three double bonds in the heterocyclic ring. In certainembodiments, at least one instance of R^(E1a) is heterocyclyl, whereinone, two, or three atoms in the heterocyclic ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, at least one instance of R^(E1a) is 3- to7-membered, monocyclic heterocyclyl. In certain embodiments, at leastone instance of R^(E1a) is 5- to 13-membered, bicyclic heterocyclyl. Incertain embodiments, at least one instance of R^(E1a) is substituted orunsubstituted aryl. In certain embodiments, at least one instance ofR^(E1a) is 6- to 14-membered aryl. In certain embodiments, at least oneinstance of R^(E1a) is 6- to 10-membered aryl. In certain embodiments,at least one instance of R^(E1a) is monocyclic aryl. In certainembodiments, at least one instance of R^(E1a) is phenyl. In certainembodiments, at least one instance of R^(E1a) is bicyclic aryl. Incertain embodiments, at least one instance of R^(E1a) is naphthyl. Incertain embodiments, at least one instance of R^(E1a) is substituted orunsubstituted heteroaryl. In certain embodiments, at least one instanceof R^(E1a) is heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, at least oneinstance of R^(E1a) is monocyclic heteroaryl. In certain embodiments, atleast one instance of R^(E1a) is 5-membered, monocyclic heteroaryl. Incertain embodiments, at least one instance of R^(E1a) is 6-membered,monocyclic heteroaryl. In certain embodiments, at least one instance ofR^(E1a) is pyridyl. In certain embodiments, at least one instance ofR^(E1a) is bicyclic heteroaryl, wherein the point of attachment may beon any atom of the bicyclic heteroaryl ring system, as valency permits.In certain embodiments, at least one instance of R^(E1a) is 9-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(E1a) is 10-membered, bicyclic heteroaryl. In certain embodiments, atleast one instance of R^(E1a) is a nitrogen protecting group whenattached to a nitrogen atom. In certain embodiments, at least oneinstance of R^(E1a) is Bn, Boc, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. Incertain embodiments, R^(E1a) is an oxygen protecting group when attachedto an oxygen atom. In certain embodiments, R^(E1a) is silyl, TBDPS,TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, orbenzoyl when attached to an oxygen atom. In certain embodiments, R^(E1a)is a sulfur protecting group when attached to a sulfur atom. In certainembodiments, R^(E1a) is acetamidomethyl, t-Bu, 3-nitro-2-pyridinesulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to asulfur atom. In certain embodiments, two instances of R^(E1a) are joinedto form substituted or unsubstituted heterocyclyl. In certainembodiments, two instances of R^(E1a) are joined to form saturated orunsaturated heterocyclyl. In certain embodiments, two instances ofR^(E1a) are joined to form heterocyclyl including one, two, or threedouble bonds in the heterocyclic ring. In certain embodiments, twoinstances of R^(E1a) are joined to form heterocyclyl, wherein one, two,or three atoms in the heterocyclic ring are independently selected fromthe group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, two instances of R^(E1a) are joined to form 3- to7-membered, monocyclic heterocyclyl. In certain embodiments, twoinstances of R^(E1a) are joined to form 5- to 13-membered, bicyclicheterocyclyl.

In certain embodiments, e is 0. In certain embodiments, e is 1. Incertain embodiments, e is 2. In certain embodiments, e is 3. In certainembodiments, e is 4. In certain embodiments, e is 5.

In certain embodiments, at least one instance of R^(E1) is halogen orsubstituted alkyl; and e is 1. In certain embodiments, at least oneinstance of R^(E1) is halogen or unsubstituted alkyl; and e is 1. Incertain embodiments, at least one instance of R^(E1) is halogen orunsubstituted C₁₋₆ alkyl; and e is 1.

Compounds of Formula (II) include substituent R^(F). In certainembodiments, R^(F) is H. In certain embodiments, R^(F) is substitutedalkyl. In certain embodiments, R^(E) is unsubstituted alkyl. In certainembodiments, R^(F) is C₁₋₁₂ alkyl. In certain embodiments, R^(E) is C₁₋₆alkyl. In certain embodiments, R^(F) is unsubstituted methyl. In certainembodiments, R^(F) is substituted methyl. In certain embodiments, R^(F)is —CH₂F. In certain embodiments, R^(F) is —CHF₂. In certainembodiments, R^(F) is —CF₃. In certain embodiments, R^(F) is Bn. Incertain embodiments, R^(F) is unsubstituted ethyl. In certainembodiments, R^(F) is substituted ethyl. In certain embodiments, R^(F)is —(CH₂)₂Ph. In certain embodiments, R^(F) is propyl. In certainembodiments, R^(F) is butyl. In certain embodiments, R^(F) is pentyl. Incertain embodiments, R^(F) is hexyl. In certain embodiments, R^(F) is—(CH₂)₁₋₅-(oxetanyl). In certain embodiments, R^(F) is of the formula:

In certain embodiments, R^(F) is —(CH₂)₁₋₅-(tetrahydrofuranyl). Incertain embodiments, R^(F) is —(CH₂)₁₋₅-(tetrahydropyranyl). In certainembodiments, R^(F) is a nitrogen protecting group. In certainembodiments, R^(F) is Bn, Boc, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, acetyl, or Ts.

In certain embodiments, R^(F) is substituted heterocyclyl. In certainembodiments, R^(F) is unsubstituted heterocyclyl. In certainembodiments, R^(F) is saturated heterocyclyl. In certain embodiments,R^(F) is unsaturated heterocyclyl. In certain embodiments, R^(F) isheterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, R^(F) is heterocyclyl,wherein one, two, or three atoms in the heterocyclic ring areindependently selected from the group consisting of nitrogen, oxygen,and sulfur. In certain embodiments, R^(F) is monocyclic heterocyclyl. Incertain embodiments, R^(F) is 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, R^(F) is bicyclic heterocyclyl. In certainembodiments, R^(F) is 5- to 13-membered, bicyclic heterocyclyl. Incertain embodiments, R^(F) is substituted or unsubstituted, 4- to7-membered, monocyclic heterocyclyl, wherein one or two atoms in theheterocyclic ring are independently oxygen or nitrogen. In certainembodiments, R^(F) is substituted oxetanyl. In certain embodiments,R^(F) is unsubstituted oxetanyl. In certain embodiments, R^(F) is of theformula:

In certain embodiments, R^(F) is of the formula:

In certain embodiments, R^(F) is of the formula:

In certain embodiments, R^(F) and R^(G) are joined to form a substitutedunsubstituted heterocyclic ring of the formula:

In certain embodiments, Ring F is substituted pyrrolidinyl. In certainembodiments, Ring F is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

wherein at least one R^(F1a) is substituted alkyl. In certainembodiments, Ring F is of the formula:

wherein at least one R^(F1a) is unsubstituted alkyl. In certainembodiments, Ring F is of the formula:

wherein at least one R^(F1a) is unsubstituted C₁₋₆ alkyl. In certainembodiments, Ring F is unsubstituted pyrrolidinyl. In certainembodiments, Ring F is of the formula:

In certain embodiments, Ring F is substituted piperidinyl. In certainembodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is unsubstituted piperidinyl. In certainembodiments, Ring F is of the formula:

In certain embodiments, Ring F is substituted or unsubstituted, 7- to10-membered, spiro bicyclic heterocyclyl, wherein two atoms in theheterocyclic ring are independently selected from the group consistingof oxygen and nitrogen. In certain embodiments, Ring F is of theformula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, R ing F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, Ring F is of the formula:

In certain embodiments, R^(F) is H. In certain embodiments, R^(F) ismethyl. In certain embodiments, R^(F) is

Compounds of Formula (II) may include one or more substituents R^(F1) onRing F. In certain embodiments, at least one instance of R^(F1) is H. Incertain embodiments, at least one instance of R^(F1) is halogen. Incertain embodiments, at least one instance of R^(F1) is F. In certainembodiments, at least one instance of R^(F1) is Cl. In certainembodiments, at least one instance of R^(F1) is Br. In certainembodiments, at least one instance of R^(F1) is I (iodine). In certainembodiments, at least one instance of R^(F1) is substituted alkyl. Incertain embodiments, at least one instance of R^(F1) is unsubstitutedalkyl. In certain embodiments, at least one instance of R^(F1) is C₁₋₁₂alkyl. In certain embodiments, at least one instance of R^(F1) is C₁₋₆alkyl. In certain embodiments, at least one instance of R^(F1) isunsubstituted methyl. In certain embodiments, at least one instance ofR^(F1) is substituted methyl. In certain embodiments, at least oneinstance of R^(F1) is —CH₂F. In certain embodiments, at least oneinstance of R^(F1) is —CHF₂. In certain embodiments, at least oneinstance of R^(F1) is —CF₃. In certain embodiments, at least oneinstance of R^(F1) is Bn. In certain embodiments, at least one instanceof R^(F1) is unsubstituted ethyl. In certain embodiments, at least oneinstance of R^(F1) is substituted ethyl. In certain embodiments, atleast one instance of R^(F1) is —(CH₂)₂Ph. In certain embodiments, atleast one instance of R^(F1) is substituted or unsubstituted propyl. Incertain embodiments, at least one instance of R^(F1) is substituted orunsubstituted butyl. In certain embodiments, at least one instance ofR^(F1) is substituted or unsubstituted pentyl. In certain embodiments,at least one instance of R^(F1) is substituted or unsubstituted hexyl.In certain embodiments, at least one instance of R^(F1) is halogen orunsubstituted C₁₋₆ alkyl. In certain embodiments, at least one instanceof R^(F1) is —OR^(F1a). In certain embodiments, at least one instance ofR^(F1) is —OR^(F1a), wherein R^(F1a) is substituted alkyl. In certainembodiments, at least one instance of R^(F1) is —OR^(F1a) whereinR^(F1a) is unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(F1) is —OR^(F1a), wherein R^(F1a) is substituted C₁₋₆alkyl. In certain embodiments, at least one instance of R^(F1) is—OR^(F1a), wherein R^(F1a) is unsubstituted C₁₋₆ alkyl. In certainembodiments, at least one instance of R^(F1) is —OPh. In certainembodiments, at least one instance of R^(F1) is —OBn. In certainembodiments, at least one instance of R^(F1) is —O(CH₂)₂Ph. In certainembodiments, at least one instance of R^(F1) is —OH. In certainembodiments, at least one instance of R^(F1) is —N(R^(F1a))₂. In certainembodiments, at least one instance of R¹ is —N(R^(F1a))₂, wherein atleast one instance of R^(F1a) is substituted alkyl. In certainembodiments, at least one instance of R^(F1) is —N(R^(F1a))₂, wherein atleast one instance of R^(E1a) is unsubstituted alkyl. In certainembodiments, at least one instance of R¹ is —N(R^(F1a))₂, wherein atleast one instance of R^(F1a) is substituted C₁₋₆ alkyl. In certainembodiments, at least one instance of R^(F1) is —N(R^(F1a))₂, wherein atleast one instance of R^(F1a) is unsubstituted C₁₋₆ alkyl. In certainembodiments, at least one instance of R^(F1) is —NH₂. In certainembodiments, at least one instance of R^(F1) is oxo. In certainembodiments, at least one instance of R^(F1) is a nitrogen protectinggroup when attached to a nitrogen atom. In certain embodiments, at leastone instance of R^(F1) is Bn, Boc, Cbz, Fmoc, trifluoroacetyl,triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom.

In certain embodiments, at least one instance of R^(F1a) is H. Incertain embodiments, at least one instance of R^(F1a) is substitutedalkyl. In certain embodiments, at least one instance of R^(F1a) isunsubstituted alkyl. In certain embodiments, at least one instance ofR^(F1a) is substituted C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(F1a) is unsubstituted C₁₋₆ alkyl. In certain embodiments,at least one instance of R^(F1a) is unsubstituted methyl. In certainembodiments, at least one instance of R^(E1a) is substituted methyl. Incertain embodiments, at least one instance of R^(F1a) is —CH₂F. Incertain embodiments, at least one instance of R^(F1a) is —CHF₂. Incertain embodiments, at least one instance of R^(F1a) is —CF₃. Incertain embodiments, at least one instance of R^(F1a) is Bn. In certainembodiments, at least one instance of R^(F1a) is unsubstituted ethyl. Incertain embodiments, at least one instance of R^(F1a) is substitutedethyl. In certain embodiments, at least one instance of R^(F1a) is—(CH₂)₂Ph. In certain embodiments, at least one instance of R^(F1a) ispropyl. In certain embodiments, at least one instance of R^(F1a) isbutyl. In certain embodiments, at least one instance of R^(F1a) ispentyl. In certain embodiments, at least one instance of R^(F1a) ishexyl. In certain embodiments, at least one instance of R^(F1a) is anitrogen protecting group when attached to a nitrogen atom. In certainembodiments, at least one instance of R^(F1a) is Bn, Boc, Cbz, Fmoc,trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to anitrogen atom. In certain embodiments, at least one instance of R^(F1a)is an oxygen protecting group when attached to an oxygen atom. Incertain embodiments, at least one instance of R^(F1a) is silyl, TBDPS,TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, orbenzoyl when attached to an oxygen atom.

In certain embodiments, two instances of R^(F1a) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(F1a) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(F1a) arejoined to form heterocyclyl including one, two, or three double bonds inthe ring of the heterocyclyl. In certain embodiments, two instances ofR^(F1a) are joined to form heterocyclyl, wherein one, two, or threeatoms in the ring of the heterocyclyl are independently selected fromthe group consisting of nitrogen, oxygen, and sulfur. In certainembodiments, two instances of R^(F1a) are joined to form 3- to7-membered, monocyclic heterocyclyl. In certain embodiments, twoinstances of R^(F1a) are joined to form 5- to 13-membered, bicyclicheterocyclyl.

In certain embodiments, f is 0. In certain embodiments, f is 1. Incertain embodiments, f is 2. In certain embodiments, f is 3.

In certain embodiments, R¹ is —N(R^(F1a))₂; and f is 1. In certainembodiments, R^(F1) is —N(unsubstituted C₁₋₆ alkyl)₂; and f is 1. Incertain embodiments, R^(F1) is oxo; and f is 1.

Compounds of Formula (II) include substituent R^(G). In certainembodiments, R^(G) is H. In certain embodiments, R^(G) is substitutedC₁₋₆ alkyl. In certain embodiments, R^(G) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(G) is unsubstituted methyl. In certainembodiments, R^(G) is substituted methyl. In certain embodiments, R^(G)is —CH₂F. In certain embodiments, R^(G) is —CHF₂. In certainembodiments, R^(G) is —CF₃. In certain embodiments, R^(G) is Bn. Incertain embodiments, R^(G) is unsubstituted ethyl. In certainembodiments, R^(G) is substituted ethyl. In certain embodiments, R^(G)is —(CH₂)₂Ph. In certain embodiments, R^(G) is propyl. In certainembodiments, R^(G) is butyl. In certain embodiments, R^(G) is pentyl. Incertain embodiments, R^(G) is hexyl. In certain embodiments, R^(G) is anitrogen protecting group. In certain embodiments, R^(G) is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

Compounds of Formula (II) include substituent R^(H). In certainembodiments, R^(H) is H. In certain embodiments, R^(H) is substitutedC₁₋₆ alkyl. In certain embodiments, R^(H) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(H) is unsubstituted methyl. In certainembodiments, R^(H) is substituted methyl. In certain embodiments, R^(H)is —CH₂F. In certain embodiments, R^(H) is —CHF₂. In certainembodiments, R^(H) is —CF₃. In certain embodiments, R^(H) is Bn. Incertain embodiments, R^(H) is unsubstituted ethyl. In certainembodiments, R^(H) is substituted ethyl. In certain embodiments, R^(H)is —(CH₂)₂Ph. In certain embodiments, R^(H) is propyl. In certainembodiments, R^(H) is butyl. In certain embodiments, R^(H) is pentyl. Incertain embodiments, R^(H) is hexyl. In certain embodiments, R^(H) is anitrogen protecting group. In certain embodiments, R^(H) is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

Compounds of Formula (II) include substituent R^(J). In certainembodiments, R^(J) is H. In certain embodiments, R^(J) is substitutedC₁₋₆ alkyl. In certain embodiments, R^(J) is unsubstituted C₁₋₆ alkyl.In certain embodiments, R^(J) is unsubstituted methyl. In certainembodiments, R^(J) is substituted methyl. In certain embodiments, R^(J)is —CH₂F. In certain embodiments, R^(J) is —CHF₂. In certainembodiments, R^(J) is —CF₃. In certain embodiments, R^(J) is Bn. Incertain embodiments, R^(J) is unsubstituted ethyl. In certainembodiments, R^(J) is substituted ethyl. In certain embodiments, R^(J)is —(CH₂)₂Ph. In certain embodiments, R^(J) is propyl. In certainembodiments, R^(J) is butyl. In certain embodiments, R^(J) is pentyl. Incertain embodiments, R^(J) is hexyl. In certain embodiments, R^(J) is anitrogen protecting group. In certain embodiments, R^(J) is Bn, Boc,Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

In certain embodiments, each one of R^(H) and R^(J) is hydrogen. Incertain embodiments, each one of R^(G), R^(H), and R^(J) is hydrogen.

Compounds of Formula (II) may include one or more R^(M) groups. Incertain embodiments, at least one instance of R^(M) is H. In certainembodiments, at least one instance of R^(M) is halogen. In certainembodiments, at least one instance of R^(M) is F. In certainembodiments, at least one instance of R^(M) is Cl. In certainembodiments, at least one instance of R^(M) is Br. In certainembodiments, at least one instance of R^(M) is I (iodine). In certainembodiments, at least one instance of R^(M) is substituted acyl. Incertain embodiments, at least one instance of R^(M) is unsubstitutedacyl. In certain embodiments, at least one instance of R^(M) issubstituted alkyl. In certain embodiments, at least one instance ofR^(M) is unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(M) is C₁₋₁₂ alkyl. In certain embodiments, at least oneinstance of R^(M) is C₁₋₆ alkyl. In certain embodiments, at least oneinstance of R^(M) is unsubstituted methyl. In certain embodiments, atleast one instance of R^(M) is substituted methyl. In certainembodiments, at least one instance of R^(M) is —CH₂F. In certainembodiments, at least one instance of R^(M) is —CHF₂. In certainembodiments, at least one instance of R^(M) is —CF₃. In certainembodiments, at least one instance of R^(M) is Bn. In certainembodiments, at least one instance of R^(M) is unsubstituted ethyl. Incertain embodiments, at least one instance of R^(M) is substitutedethyl. In certain embodiments, at least one instance of R^(M) is—(CH₂)₂Ph. In certain embodiments, at least one instance of R^(M) ispropyl. In certain embodiments, at least one instance of R^(M) is butyl.In certain embodiments, at least one instance of R^(M) is pentyl. Incertain embodiments, at least one instance of R^(M) is hexyl. In certainembodiments, at least one instance of R^(M) is halogen or substituted orunsubstituted C₁₋₆ alkyl. In certain embodiments, at least one instanceof R^(M) is substituted alkenyl. In certain embodiments, at least oneinstance of R^(M) is unsubstituted alkenyl. In certain embodiments, atleast one instance of R^(M) is vinyl. In certain embodiments, at leastone instance of R^(M) is substituted alkynyl. In certain embodiments, atleast one instance of R^(M) is unsubstituted alkynyl. In certainembodiments, at least one instance of R^(M) is ethynyl. In certainembodiments, at least one instance of R^(M) is substituted carbocyclyl.In certain embodiments, at least one instance of R^(M) is unsubstitutedcarbocyclyl. In certain embodiments, at least one instance of R^(M) issaturated carbocyclyl. In certain embodiments, at least one instance ofR^(M) is unsaturated carbocyclyl. In certain embodiments, at least oneinstance of R^(M) is carbocyclyl including one, two, or three doublebonds in the carbocyclic ring. In certain embodiments, at least oneinstance of R^(M) is monocyclic carbocyclyl. In certain embodiments, atleast one instance of R^(M) is 3- to 7-membered, monocyclic carbocyclyl.In certain embodiments, at least one instance of R^(M) is cylcopropyl.In certain embodiments, at least one instance of R^(M) is cyclobutyl. Incertain embodiments, at least one instance of R^(M) is cyclopentyl. Incertain embodiments, at least one instance of R^(M) is cyclohexyl. Incertain embodiments, at least one instance of R^(M) is cycloheptyl. Incertain embodiments, at least one instance of R^(M) is bicycliccarbocyclyl. In certain embodiments, at least one instance of R^(M) is5- to 13-membered, bicyclic carbocyclyl. In certain embodiments, atleast one instance of R^(M) is substituted heterocyclyl. In certainembodiments, at least one instance of R^(M) is unsubstitutedheterocyclyl. In certain embodiments, at least one instance of R^(M) issaturated heterocyclyl. In certain embodiments, at least one instance ofR^(M) is unsaturated heterocyclyl. In certain embodiments, at least oneinstance of R^(M) is heterocyclyl including one, two, or three doublebonds in the heterocyclic ring. In certain embodiments, at least oneinstance of R^(M) is heterocyclyl, wherein one, two, or three atoms inthe heterocyclic ring are independently selected from the groupconsisting of nitrogen, oxygen, and sulfur. In certain embodiments, atleast one instance of R^(M) is monocyclic heterocyclyl. In certainembodiments, at least one instance of R^(M) is 3- to 7-membered,monocyclic heterocyclyl. In certain embodiments, at least one instanceof R^(M) is bicyclic heterocyclyl. In certain embodiments, at least oneinstance of R^(M) is 5- to 13-membered, bicyclic heterocyclyl. Incertain embodiments, at least one instance of R^(M) is substituted aryl.In certain embodiments, at least one instance of R^(M) is unsubstitutedaryl. In certain embodiments, at least one instance of R^(M) is 6- to14-membered aryl. In certain embodiments, at least one instance of R^(M)is 6- to 10-membered aryl. In certain embodiments, at least one instanceof R^(M) is substituted phenyl. In certain embodiments, at least oneinstance of R^(M) is unsubstituted phenyl. In certain embodiments, atleast one instance of R^(M) is substituted naphthyl. In certainembodiments, at least one instance of R^(M) is unsubstituted naphthyl.In certain embodiments, at least one instance of R^(M) is substitutedheteroaryl. In certain embodiments, at least one instance of R^(M) isunsubstituted heteroaryl. In certain embodiments, at least one instanceof R^(M) is heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, at least oneinstance of R^(M) is monocyclic heteroaryl. In certain embodiments, atleast one instance of R^(M) is 5-membered, monocyclic heteroaryl. Incertain embodiments, at least one instance of R^(M) is 6-membered,monocyclic heteroaryl. In certain embodiments, at least one instance ofR^(M) is pyridyl. In certain embodiments, at least one instance of R^(M)is bicyclic heteroaryl, wherein the point of attachment may be on anyatom of the bicyclic heteroaryl ring system, as valency permits. Incertain embodiments, at least one instance of R^(M) is 9-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(M) is 10-membered, bicyclic heteroaryl. In certain embodiments, atleast one instance of R^(M) is —OR^(M1). In certain embodiments, atleast one instance of R^(M) is —OMe. In certain embodiments, at leastone instance of R^(M) is —OEt. In certain embodiments, at least oneinstance of R^(M) is —OPr. In certain embodiments, at least one instanceof R^(M) is —OBu. In certain embodiments, at least one instance of R^(M)is —O(pentyl). In certain embodiments, at least one instance of R^(M) is—O(hexyl). In certain embodiments, at least one instance of R^(M) is—OPh. In certain embodiments, at least one instance of R^(M) is —OBn. Incertain embodiments, at least one instance of R^(M) is —O(CH₂)₂Ph. Incertain embodiments, at least one instance of R^(M) is —OH. In certainembodiments, at least one instance of R^(M) is —SR^(M1). In certainembodiments, at least one instance of R^(M) is —SH. In certainembodiments, at least one instance of R^(M) is —N(R^(M1))₂. In certainembodiments, at least one instance of R^(M) is —NH₂. In certainembodiments, at least one instance of R^(M) is —CN. In certainembodiments, at least one instance of R^(M) is —SCN. In certainembodiments, at least one instance of R^(M) is —C(═NR^(M1))R^(M1),—C(═NR^(M1))OR^(M1), or —C(═NR^(M1))N(R^(M1))₂. In certain embodiments,at least one instance of R^(M) is —C(═O)R^(M1), —C(═O)OR^(M1), or—C(═O)N(R^(M1))₂. In certain embodiments, at least one instance of R^(M)is —NO₂. In certain embodiments, at least one instance of R^(M) is—NR^(M1)C(═O)R^(M1), —NR^(M1)C(═O)OR^(M1), or —NR^(M1)C(═O)N(R^(M1))₂.In certain embodiments, at least one instance of R^(M) is —OC(═O)R^(M1),—OC(═O)OR^(M1), or —OC(═O)N(R^(M1))₂.

In certain embodiments, at least one instance of R^(M) is hydrogen,halogen, or unsubstituted alkyl. In certain embodiments, at least oneinstance of R^(M) is hydrogen, halogen, or unsubstituted C₁₋₆ alkyl. Incertain embodiments, at least one instance of R^(M) is halogen orunsubstituted alkyl. In certain embodiments, at least one instance ofR^(M) is halogen or unsubstituted C₁₋₆ alkyl. In certain embodiments,R^(M) is halogen; and p is 1. In certain embodiments, R^(M) isunsubstituted C₁₋₆ alkyl; and p is 1. In certain embodiments, eachinstance of R^(M) is independently halogen or unsubstituted C₁₋₆ alkyl;and p is 2.

In compounds of Formula (I), two R^(M) groups may be joined to formsubstituted or unsubstituted carbocyclyl. In certain embodiments, twoinstances of R^(M) are joined to form saturated or unsaturatedcarbocyclyl. In certain embodiments, two instances of R^(M) are joinedto form carbocyclyl including one, two, or three double bonds in thecarbocyclic ring. In certain embodiments, two instances of R^(M) arejoined to form 3- to 7-membered, monocyclic carbocyclyl. In certainembodiments, two instances of R^(M) are joined to form 3-memberedcarbocyclyl. In certain embodiments, two instances of R^(M) are joinedto form 4-membered carbocyclyl. In certain embodiments, two instances ofR^(M) are joined to form 5-membered carbocyclyl. In certain embodiments,two instances of R^(M) are joined to form 6-membered carbocyclyl. Incertain embodiments, two instances of R^(M) are joined to form7-membered carbocyclyl. In certain embodiments, two instances of R^(M)are joined to form 5- to 13-membered, bicyclic carbocyclyl.

In certain embodiments, two instances of R^(M) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(M) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(M) are joinedto form heterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, two instances of R^(M) arejoined to form heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, two instancesof R^(M) are joined to form 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, two instances of R^(M) are joined to form 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, two instances of R^(M) are joined to formsubstituted or unsubstituted aryl. In certain embodiments, two instancesof R^(M) are joined to form 6- to 14-membered aryl. In certainembodiments, two instances of R^(M) are joined to form 6- to 10-memberedaryl. In certain embodiments, two instances of R^(M) are joined to formmonocyclic aryl. In certain embodiments, two instances of R^(M) arejoined to form phenyl. In certain embodiments, two instances of R^(M)are joined to form bicyclic aryl. In certain embodiments, two instancesof R^(M) are joined to form naphthyl.

In certain embodiments, two instances of R^(M) are joined to formsubstituted or unsubstituted heteroaryl. In certain embodiments, twoinstances of R^(M) are joined to form monocyclic heteroaryl, whereinone, two, or three atoms in the heteroaryl ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, two instances of R^(M) are joined to form5-membered, monocyclic heteroaryl. In certain embodiments, two instancesof R^(M) are joined to form pyrrolyl. In certain embodiments, twoinstances of R^(M) are joined to form 6-membered, monocyclic heteroaryl.In certain embodiments, two instances of R^(M) are joined to formpyridyl. In certain embodiments, two instances of R^(M) are joined toform bicyclic heteroaryl, wherein one, two, three, or four atoms in theheteroaryl ring are independently selected from the group consisting ofnitrogen, oxygen, and sulfur. In certain embodiments, two instances ofR^(M) are joined to form 9-membered, bicyclic heteroaryl. In certainembodiments, two instances of R^(M) are joined to form 10-membered,bicyclic heteroaryl.

In certain embodiments, at least one instance of R^(M1) is H. In certainembodiments, at least one instance of R^(M1) is substituted acyl. Incertain embodiments, at least one instance of R^(M1) is unsubstitutedacyl. In certain embodiments, at least one instance of R^(M1) is acetyl.In certain embodiments, at least one instance of R^(M1) is substitutedalkyl. In certain embodiments, at least one instance of R^(M1) isunsubstituted alkyl. In certain embodiments, at least one instance ofR^(M1) is C₁₋₁₂ alkyl. In certain embodiments, at least one instance ofR^(M1) is C₁₋₆ alkyl. In certain embodiments, at least one instance ofR^(M1) is methyl. In certain embodiments, at least one instance ofR^(M1) is ethyl. In certain embodiments, at least one instance of R^(M1)is propyl. In certain embodiments, at least one instance of R^(M1) isbutyl. In certain embodiments, at least one instance of R^(M1) ispentyl. In certain embodiments, at least one instance of R^(M1) ishexyl. In certain embodiments, at least one instance of R^(M1) issubstituted alkenyl. In certain embodiments, at least one instance ofR^(M1) is unsubstituted alkenyl. In certain embodiments, at least oneinstance of R^(M1) is vinyl. In certain embodiments, at least oneinstance of R^(M1) is substituted alkynyl. In certain embodiments, atleast one instance of R^(M1) is unsubstituted alkynyl. In certainembodiments, at least one instance of R^(M1) is ethynyl. In certainembodiments, at least one instance of R^(M1) is substituted carbocyclyl.In certain embodiments, at least one instance of R^(M1) is unsubstitutedcarbocyclyl. In certain embodiments, at least one instance of R^(M1) issaturated carbocyclyl. In certain embodiments, at least one instance ofR^(M1) is unsaturated carbocyclyl. In certain embodiments, at least oneinstance of R^(M1) is carbocyclyl including one, two, or three doublebonds in the carbocyclic ring. In certain embodiments, at least oneinstance of R^(M1) is 3- to 7-membered, monocyclic carbocyclyl. Incertain embodiments, at least one instance of R^(M1) is cylcopropyl. Incertain embodiments, at least one instance of R^(M1) is cyclobutyl. Incertain embodiments, at least one instance of R^(M1) is cyclopentyl. Incertain embodiments, at least one instance of R^(M1) is cyclohexyl. Incertain embodiments, at least one instance of R^(M1) is cycloheptyl. Incertain embodiments, at least one instance of R^(M1) is 5- to13-membered, bicyclic carbocyclyl. In certain embodiments, at least oneinstance of R^(M1) is substituted heterocyclyl. In certain embodiments,at least one instance of R^(M1) is unsubstituted heterocyclyl. Incertain embodiments, at least one instance of R^(M1) is saturatedheterocyclyl. In certain embodiments, at least one instance of R^(M1) isunsaturated heterocyclyl. In certain embodiments, at least one instanceof R^(M1) is heterocyclyl including one, two, or three double bonds inthe heterocyclic ring. In certain embodiments, at least one instance ofR^(M1) is heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, at least oneinstance of R^(M1) is 3- to 7-membered, monocyclic heterocyclyl. Incertain embodiments, at least one instance of R^(M1) is 5- to13-membered, bicyclic heterocyclyl. In certain embodiments, at least oneinstance of R^(M1) is substituted or unsubstituted aryl. In certainembodiments, at least one instance of R^(M1) is 6- to 14-membered aryl.In certain embodiments, at least one instance of R^(M1) is 6- to10-membered aryl. In certain embodiments, at least one instance ofR^(M1) is monocyclic aryl. In certain embodiments, at least one instanceof R^(M1) is phenyl. In certain embodiments, at least one instance ofR^(M1) is bicyclic aryl. In certain embodiments, at least one instanceof R^(M1) is naphthyl. In certain embodiments, at least one instance ofR^(M1) is substituted or unsubstituted heteroaryl. In certainembodiments, at least one instance of R^(M1) is heteroaryl, wherein one,two, three, or four atoms in the heteroaryl ring are independentlyselected from the group consisting of nitrogen, oxygen, and sulfur. Incertain embodiments, at least one instance of R^(M1) is monocyclicheteroaryl. In certain embodiments, at least one instance of R^(M1) is5-membered, monocyclic heteroaryl. In certain embodiments, at least oneinstance of R^(M1) is 6-membered, monocyclic heteroaryl. In certainembodiments, at least one instance of R^(M1) is pyridyl. In certainembodiments, at least one instance of R^(M1) is bicyclic heteroaryl,wherein the point of attachment may be on any atom of the bicyclicheteroaryl ring system, as valency permits. In certain embodiments, atleast one instance of R^(M1) is 9-membered, bicyclic heteroaryl. Incertain embodiments, at least one instance of R^(M1) is 10-membered,bicyclic heteroaryl. In certain embodiments, at least one instance ofR^(M1) is a nitrogen protecting group when attached to a nitrogen atom.In certain embodiments, at least one instance of R^(M1) is Bn, Boc, Cbz,Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to anitrogen atom. In certain embodiments, R^(M1) is an oxygen protectinggroup when attached to an oxygen atom. In certain embodiments, R^(M1) issilyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl,pivaloyl, or benzoyl when attached to an oxygen atom. In certainembodiments, R^(M1) is a sulfur protecting group when attached to asulfur atom. In certain embodiments, R^(M1) is acetamidomethyl, t-Bu,3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethylwhen attached to a sulfur atom.

In certain embodiments, two instances of R^(M1) are joined to formsubstituted or unsubstituted heterocyclyl. In certain embodiments, twoinstances of R^(M1) are joined to form saturated or unsaturatedheterocyclyl. In certain embodiments, two instances of R^(M1) are joinedto form heterocyclyl including one, two, or three double bonds in theheterocyclic ring. In certain embodiments, two instances of R^(M1) arejoined to form heterocyclyl, wherein one, two, or three atoms in theheterocyclic ring are independently selected from the group consistingof nitrogen, oxygen, and sulfur. In certain embodiments, two instancesof R^(M1) are joined to form 3- to 7-membered, monocyclic heterocyclyl.In certain embodiments, two instances of R^(M1) are joined to form 5- to13-membered, bicyclic heterocyclyl.

In certain embodiments, p is 0. In certain embodiments, p is 1. Incertain embodiments, p is 2. In certain embodiments, p is 3. In certainembodiments, p is 4.

In compounds of Formula (II), the U and V moieties may be directlyconnected, or there may be one or more methylene groups between U and V.In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 5.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, the compound of Formula (II) is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

The present invention also provides the compound of Formula (III):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

The present invention further provides the compound of Formula (IV):

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

Compounds of the invention may be crystalline. In certain embodiments,the compounds of the invention are monocrystalline. In certainembodiments, the compounds of the invention are polycrystalline.

Compounds of the invention may also have a relatively low aqueoussolubility (i.e., a solubility in water, optionally with one or morebuffers). For example, compounds of the invention may have an aqueoussolubility of less than about or equal to about 3 mg/mL, less than about1 mg/mL, less than about 0.3 mg/mL, less than about 0.1 mg/mL, less thanabout 0.03 mg/mL, less than about 0.01 mg/mL, less than about 1 μg/mL,less than about 0.1 μg/mL, less than about 0.01 μg/mL, less than about 1ng/mL, less than about 0.1 ng/mL, or less than about 0.01 ng/mL at 25°C. In some embodiments, the compounds of the invention have an aqueoussolubility of at least about 1 μg/mL, at least about 10 pg/mL, at leastabout 0.1 ng/mL, at least about 1 ng/mL, at least about 10 ng/mL, atleast about 0.1 μg/mL, at least about 1 μg/mL, at least about 3 μg/mL,at least about 0.01 mg/mL, at least about 0.03 mg/mL, at least about 0.1mg/mL, at least about 0.3 mg/mL, at least about 1.0 mg/mL, or at leastabout 3 mg/mL at 25° C. Combinations of the above-noted ranges arepossible (e.g., an aqueous solubility of at least about 10 pg/mL andless than about 1 mg/mL). Other ranges are also possible. The compoundsof the invention may have these or other ranges of aqueous solubilitiesat any point throughout the pH range (e.g., at about pH 7 or from pH 1to pH 14).

Compounds of the invention may be suitable for being processed intomucus-penetrating pharmaceutical compositions (e.g., particles orcrystals). In certain embodiments, the compounds of the invention aresuitable for milling (e.g., nano-milling). In certain embodiments, thecompounds of the invention are suitable for precipitation (e.g.,microprecipitation, nanoprecipitation, crystallization, or controlledcrystallization). In certain embodiments, the compounds of the inventionare suitable for emulsification. In certain embodiments, the compoundsof the invention are suitable for freeze-drying.

The compounds of the invention include the compounds described herein(e.g., compounds of any one of Formulae (I)-(IV)), and pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, co-crystals,tautomers, stereoisomers, isotopically labeled derivatives, and prodrugsthereof. In certain embodiments, the compounds of the invention arecompounds of Formula (I) and pharmaceutically acceptable salts thereof.In certain embodiments, the compounds of the invention are compounds ofFormula (II) and pharmaceutically acceptable salts thereof. In certainembodiments, the compounds of the invention are the compound of Formula(III) and pharmaceutically acceptable salts thereof. In certainembodiments, the compounds of the invention are the compound of Formula(IV) and pharmaceutically acceptable salts thereof. The compounds of theinvention may be useful in treating and/or preventing a disease (e.g., adisease associated with abnormal angiogenesis and/or aberrant signalingof a growth factor signaling pathway (e.g., VEGF)) in a subject in needthereof. The compounds of the invention may also be useful in inhibitingabnormal angiogenesis and/or aberrant signaling of a growth factorpathway in a subject and/or cell.

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprising acompound of the invention (e.g., a compound of any one of Formulae(I)-(IV), or a pharmaceutically acceptable salt, solvate, hydrate,polymorph, co-crystal, tautomer, stereoisomer, isotopically labeledderivative, or prodrug thereof), and optionally a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition of the invention comprises a compound of Formula (I), or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical composition of the invention comprises a compound ofFormula (II), or a pharmaceutically acceptable salt thereof, andoptionally a pharmaceutically acceptable excipient. In certainembodiments, the pharmaceutical composition of the invention comprisesthe compound of Formula (III), or a pharmaceutically acceptable saltthereof, and optionally a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition of the inventioncomprises the compound of Formula (IV), or a pharmaceutically acceptablesalt thereof, and optionally a pharmaceutically acceptable excipient.

In certain embodiments, the compound of the invention is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount. In certain embodiments, the effective amount is anamount effective for treating and/or preventing a disease. In certainembodiments, the effective amount is an amount effective for treating adisease. In certain embodiments, the effective amount is an amounteffective for treating and/or preventing a disease associated withaberrant signaling of a growth factor. In certain embodiments, theeffective amount is an amount effective for treating a diseaseassociated with aberrant signaling of a growth factor. In certainembodiments, the effective amount is an amount effective for treatingand/or preventing a disease associated with aberrant signaling ofvascular endothelial growth factor (VEGF). In certain embodiments, theeffective amount is an amount effective for treating a diseaseassociated with aberrant signaling of vascular endothelial growth factor(VEGF). In certain embodiments, the effective amount is an amounteffective for treating and/or preventing a disease associated withabnormal angiogenesis, such as cancer, benign neoplasm, atherosclerosis,hypertension, inflammatory disease, rheumatoid arthritis, maculardegeneration, choroidal neovascularization, retinal neovascularization,and diabetic retinopathy. In certain embodiments, the effective amountis an amount effective to treat cancer (e.g., an ocular cancer). Incertain embodiments, the effective amount is an amount effective totreat macular degeneration.

An effective amount of a compound may vary from about 0.001 mg/kg toabout 1000 mg/kg in one or more dose administrations for one or severaldays (depending on the mode of administration). In certain embodiments,the effective amount per dose varies from about 0.001 mg/kg to about1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, andfrom about 10.0 mg/kg to about 150 mg/kg.

An effective amount of a compound of the invention may inhibit abnormalangiogenesis and/or aberrant signaling of a growth factor by at leastabout 10%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, or at least about 90%. An effective amount of a compound ofthe invention may inhibit abnormal angiogenesis and/or aberrantsignaling of a growth factor by less than about 90%, less than about80%, less than about 70%, less than about 60%, less than about 50%, lessthan about 40%, less than about 30%, less than about 20%, or less thanabout 10%. Combinations of the ranges described herein (e.g., at least20% and less than 50%) are also within the scope of the invention. Incertain embodiments, an effective amount of a compound of the inventioninhibits abnormal angiogenesis and/or aberrant signaling of a growthfactor by a percentage or a range of percentage described herein,compared to normal angiogenesis and/or signaling.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound described herein(i.e., the “active ingredient”) into association with a carrier orexcipient, and/or one or more other accessory ingredients, and then, ifnecessary and/or desirable, shaping, and/or packaging the product into adesired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.001% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g., acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays(e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminumsilicate)), long chain amino acid derivatives, high molecular weightalcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.,carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60),polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate(Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate(Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80),polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45),polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g., Cremophor®),polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer P-188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starchpaste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g., acacia, sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate(Veegum®), and larch arabogalactan), alginates, polyethylene oxide,polyethylene glycol, inorganic calcium salts, silicic acid,polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, antiprotozoanpreservatives, alcohol preservatives, acidic preservatives, and otherpreservatives. In certain embodiments, the preservative is anantioxidant. In other embodiments, the preservative is a chelatingagent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®,Kathon®, and Euxyl®.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. The formulation can also be prepared under asepticconditions or sterilized with heat or irradiation.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol, or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of encapsulating agents which can be usedinclude polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Additionally, thepresent invention contemplates the use of transdermal patches, whichoften have the added advantage of providing controlled delivery of anactive ingredient to the body. Such dosage forms can be prepared, forexample, by dissolving and/or dispensing the active ingredient in theproper medium. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing theactive ingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof.Alternatively or additionally, conventional syringes can be used in theclassical mantoux method of intradermal administration. Jet injectiondevices which deliver liquid vaccines to the dermis via a liquid jetinjector and/or via a needle which pierces the stratum corneum andproduces a jet which reaches the dermis are suitable. Jet injectiondevices are described, for example, in U.S. Pat. Nos. 5,480,381;5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627;5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; andPCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions. Topicallyadministrable formulations may, for example, comprise from about 0.001%to about 50% (w/w) active ingredient, although the concentration of theactive ingredient can be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration. Sucha formulation may comprise dry particles which comprise the activeingredient and which have a diameter in the range from about 0.5 toabout 7 microns, or from about 1 to about 6 microns. Such compositionsare conveniently in the form of dry powders for administration using adevice comprising a dry powder reservoir to which a stream of propellantcan be directed to disperse the powder and/or using a self-propellingsolvent/powder dispensing container such as a device comprising theactive ingredient dissolved and/or suspended in a low-boiling propellantin a sealed container. Such powders comprise particles wherein at least98% of the particles by weight have a diameter greater than 0.5nanometers and at least 95% of the particles by number have a diameterless than 20 microns. Alternatively, at least 95% of the particles byweight have a diameter greater than 1 nanometer and at least 90% of theparticles by number have a diameter less than 15 microns. In someembodiments the majority of the particles have a diameter in the rangeof 1-10 microns. In some embodiments, the majority of the particles havea diameter in the range of 1-5 microns. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.001 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.01 to about 200 microns.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition of theinvention. Another formulation suitable for intranasal administration isa coarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.001% (w/w) to as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition of the invention can beprepared, packaged, and/or sold in a formulation for oraladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for pulmonary administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.01 to about 200 microns,and may further comprise one or more of the additional ingredientsdescribed herein.

Formulations described herein may also be delivered via buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.001 to 50% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, a 0.001-10.0% (w/w) solution and/or suspension of theactive ingredient in an aqueous or oily liquid carrier or excipient.Such drops may further comprise buffering agents, salts, and/or one ormore other of the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are alsocontemplated as being within the scope of this invention.

A pharmaceutical composition of the invention may also be formulated forophthalmic administration; by injection in any acceptable form (e.g.,intravenous, intraperitoneal, intramuscular, subcutaneous, parenteral,epidural, intravitreal or perocular); and by implant or the use ofreservoirs (e.g., subcutaneous pump, intrathecal pump, suppository,biodegradable delivery system, non-biodegradable delivery system andother implanted extended or slow release device or formulation). Apharmaceutical composition of the invention may also be formulated foradministration by the ophthalmic mucous membrane route, such as, forexample, eye drops or eye ointments. These formulations may be preparedby conventional means, and, if desired, the subject compositions may bemixed with any conventional additive, such as a buffering orpH-adjusting agent, tonicity adjusting agents, viscosity modifiers,suspension stabilizers, preservatives, and other pharmaceuticalexcipients. In addition, in certain embodiments, subject compositionsdescribed herein may be lyophilized or subjected to another appropriatedrying technique such as spray drying.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease being treated and theseverity of the disorder; the activity of the specific active ingredientemployed; the specific composition employed; the age, body weight,general health, sex, and diet of the subject; the time ofadministration, route of administration, and rate of excretion of thespecific active ingredient employed; the duration of the treatment;drugs used in combination or coincidental with the specific activeingredient employed; and like factors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, injections, includingintravenous administration (e.g., systemic intravenous injection),regional administration via blood and/or lymph supply, and/or directadministration to an affected site, including topical administration. Ingeneral, the most appropriate route of administration will depend upon avariety of factors including the nature of the agent (e.g., itsstability in the environment of the gastrointestinal tract), and/or thecondition of the subject (e.g., whether the subject is able to tolerateoral administration). In certain embodiments, the compound orpharmaceutical composition of the invention is suitable for topicaladministration to the eye of a subject.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. The desired dosage can be delivered three times a day, twotimes a day, once a day, every other day, every third day, every week,every two weeks, every three weeks, or every four weeks. In certainembodiments, the desired dosage can be delivered using multipleadministrations (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or more administrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds described herein may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 1000 mg/kg,from about 0.01 mg/kg to about 500 mg/kg, preferably from about 0.1mg/kg to about 400 mg/kg, preferably from about 0.5 mg/kg to about 300mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.1 mg/kg toabout 10 mg/kg, and more preferably from about 1 mg/kg to about 25mg/kg, of subject body weight per day, one or more times a day, toobtain the desired therapeutic and/or prophylactic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents (e.g., therapeutically and/or prophylacticallyactive agents). The compounds or compositions can be administered incombination with additional pharmaceutical agents that improve theiractivity (e.g., activity in preventing and/or treating a diseaseassociated with aberrant signaling of a growth factor (e.g., VEGF) orwith abnormal angiogenesis in a subject, in inhibiting aberrantsignaling of a growth factor (e.g., VEGF) in a subject or cell, or ininhibiting abnormal angiogenesis in a subject), bioavailability, reduceand/or modify their metabolism, inhibit their excretion, and/or modifytheir distribution within the body of a subject. It will also beappreciated that the therapy employed may achieve a desired effect forthe same disorder, and/or it may achieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies. Pharmaceutical agentsinclude therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Pharmaceutical agents includesmall organic molecules such as drug compounds (e.g., compounds approvedfor human or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful for treating and/or preventing a diseasedescribed herein. Each additional pharmaceutical agent may beadministered at a dose and/or on a time schedule determined for thatpharmaceutical agent. The additional pharmaceutical agents may also beadministered together with each other and/or with the compound orcomposition described herein in a single dose or administered separatelyin different doses. The particular combination to employ in a regimenwill take into account compatibility of the inventive compound with theadditional pharmaceutical agent(s) and/or the desired therapeutic and/orprophylactic effect to be achieved. In general, it is expected that theadditional pharmaceutical agent(s) utilized in combination be utilizedat levels that do not exceed the levels at which they are utilizedindividually. In some embodiments, the levels utilized in combinationwill be lower than those utilized individually.

The additional pharmaceutical agents include, but are not limited to,anti-proliferative agents (e.g., anti-cancer agents), anti-angiogenesisagents, anti-inflammatory agents, immunosuppressants, anti-bacterialagents, anti-viral agents, anti-diabetic agents, anti-allergic agents,and pain-relieving agents. In certain embodiments, the additionalpharmaceutical agent is a growth factor inhibitor. In certainembodiments, the additional pharmaceutical agent is a VEGF inhibitor. Incertain embodiments, the additional pharmaceutical agent is anangiogenesis inhibitor. In certain embodiments, the additionalpharmaceutical agent is an endogenous angiogenesis inhibitor (e.g.,vascular endothelial growth factor receptor 1 (VEGFR-1, e.g., pazopanib(Votrient®), cediranib (Recentin®), tivozanib (AV-951), axitinib(Inlyta®), semaxanib), HER2 (lapatinib (Tykerb®, Tyverb®), linifanib(ABT-869), MGCD-265, and KRN-633), VEGFR-2 (e.g., regorafenib(BAY73-4506), telatinib (BAY 57-9352), vatalanib (PTK787, PTK/ZK), MGCD-265,OSI-930, and KRN-633), NRP-1, angiopoietin 2, TSP-1, TSP-2, angiostatin,endostatin, vasostatin, calreticulin, platelet factor-4, TIMP, CDAI,Meth-1, Meth-2, IFN-α, IFN-β, IFN-γ, CXCL10, IL-4, IL-12, IL-18,prothrombin (kringle domain-2), antithrombin III fragment, prolactin,VEGI, SPARC, osteopontin, maspin, canstatin, a proliferin-relatedprotein, sorafenib (Nexavar®), and restin). In certain embodiments, theadditional pharmaceutical agent is an exogenous angiogenesis inhibitor(e.g., bevacizumab, itraconazole, carboxyamidotriazole, TNP-470, CM101,IFN-α, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, aVEGFR antagonist, an angiostatic steroid, an angiostaticsteroid+heparin, a cartilage-derived angiogenesis inhibitory factor, amatrix metalloproteinase inhibitor, angiostatin, endostatin,2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide,thrombospondin, prolactin, a αvβ₃ inhibitor, linomide, and tasquinimod).In certain embodiments, the additional pharmaceutical agent is acorticosteroid, a receptor tyrosine kinase (RTK) inhibitor, acyclooxygenase (COX) inhibitor, a prostaglandin analog, a non-steroidalanti-inflammatory drug (NSAID), a beta blocker, or a carbonic anhydraseinhibitor. In certain embodiments, the additional pharmaceutical agentis a pharmaceutical agent useful for treating and/or preventing AMD,such as verteporfin (e.g., Chlorin®, Visudyne®), thalidomide (e.g.,Ambiodry®, Synovir®, Thalomid®), talaporfin sodium (e.g., Aptocine®,Laserphyrin®, Litx®), ranibizumab (e.g., Lucentis®), pegaptaniboctasodium (e.g., Macugen®, Macuverse®), isopropyl unoprostone (e.g.,Ocuseva®, Rescula®), interferon beta (e.g., Feron®), fluocinoloneacetonide (e.g., Envision TD®, Retisert®), everolimus (e.g., Afinitor®,Certican®, Votubia®, Zortress®), eculizumab (e.g., Solaris®, Soliris®),dexamethasone (e.g., Osurdex®, Ozurdex®, Posurdex®, Surodex®),canakinumab (e.g., Ilaris®), bromfenac (Bromday®), ophthalmic (e.g.,Bronac®, Bronuck®, Xibrom®, Yellox®), brimonidine (e.g., Alphagan®,Bromoxidine®, Enidin®), anecortave acetate (e.g., Retaane®, Edex®,Prostavasin®, Rigidur®, Vasoprost®, Viridal®), aflibercept ophthalmicsolution (e.g., Eyelea®, Eylea®, VEGF-Trap-Eye®), ocriplasmin (e.g.,Iluvien®, Medidur®, Medidur FA®), sirolimus (e.g., Perceiva®), NT-501,KH-902, fosbretabulin tromethamine (e.g., Zybrestat®), AL-8309,aganirsen (e.g., Norvess®), volociximab (e.g., Opthotec®), triamcinolone(e.g., Icon Bioscience), TRC-105, Burixafor (e.g., TG-0054), TB-403(e.g., R-7334), squalamine (e.g., Evizon®), SB-623, S-646240,RTP-801i-14 (e.g., PF-4523655), RG-7417 (e.g., FCFD-4514S), AL-78898A(e.g., POT-4), PG-11047 (e.g., CGC-11047), pazopanib hydrochloride,sonepcizumab (e.g., Asonep®, Sphingomab®), padeliporfin (e.g., Stakel®),OT-551, ontecizumab, NOX-A12, hCNS-SC, Neu-2000, NAFB001, MA09-hRPE,LFG-316, iCo-007 (e.g., ISIS-13650), hI-conl, GSK-933776A, GS-6624(e.g., AB-0024), ESBA-1008, epitalon, E-10030 (e.g., ARC-127),dalantercept, MP-0112, CNTO-2476, CERE-120, AAV-NTN, CCX-168,Brimonidine-DDS, bevasiranib sodium (e.g., Cand5), bertilimumab,AVA-101, ALG-1001, AL-39324, AGN-150998, ACU-4429, A6 (e.g., Paralit®),TT-30, sFLT-01 gene therapy, RetinoStat®, PRS-050 (e.g., Angiocal®),PF-4382923, Palomid-529, MC-1101, GW-824575, Dz13 (e.g., TRC-093), D93,CDX-1135 (e.g., TP10), ATL-1103, ARC-1905, XV-615, wet-AMD antibodies(e.g., pSivida), VEGF/rGel, VAR-10200, VAL-566-620-MULTI, TKI, TK-001,STP-601, dry AMD stem cell therapy (e.g., EyeCyte), OpRegen, SMT-D004,SAR-397769, RTU-007, RST-001, RGNX-004, RFE-007-CAI, retinal degeneratonprogramme (e.g., Orphagen), retinal cells (e.g., ISCO), ReN003, PRM-167,ProDex, Photoswitches (e.g., Photoswitch Biosciences), Parkinson'stherapy, OMS-721, OC-10X, NV. AT.08, NT-503, NAFB002, NADPH oxidaseinhibitors (e.g., Alimera Sciences), MC-2002, lycium anti-angiogenicproteoglycan, IXSVEGF, integrin inhibitors, GW-771806, GBS-007, Eos-013,EC-400, dry-AMD therapy (e.g., Neuron Systems), CGEN-25017, CERE-140,AP-202, AMD therapy (e.g., Valens Therapeutics), AMD therapy (e.g.,Amarna Therapeutics), AMD RNAi therapy (e.g., RXi), ALK-001, AMD therapy(e.g., Aciont), AC-301, 4-IPP, zinc-monocysteine complexes (e.g.,Adeona), vatalanib, TG-100-344, prinomastat, PMX-53, Neovastat,mecamylamine, JSM-6427, JPE-1375, CereCRIB, BA-285, ATX-S10, AG-13958,verteporfin/alphavβ3 conjugate, VEGF/rGel, VEGF-saporin, VEGF-R2antagonist (e.g., Allostera), VEGF inhibitors (e.g., Santen), VEGFantagonists (e.g., Ark), Vangiolux®, Triphenylmethanes (e.g., Alimera),TG-100-801, TG-100-572, TA-106, T2-TrpRS, SU-0879, stem cell therapy(e.g., Pfizer and UCL), SOD mimetics (e.g., Inotek), SHEF-1, rostaporfin(e.g., Photrex®, Purlytin®, SnET2), RNA interference (e.g., Idera andMerck), rhCFHp (e.g., Optherion), retino-NPY, retinitis pigmentosatherapy (e.g., Mimetogen), AMD gene therapy (e.g., Novartis), retinalgene therapy (e.g., Genzyme), AMD gene therapy (e.g., Copernicus),retinal dystrophy ther (e.g., Fovea and Genzyme), Ramot project No.K-734B, PRS-055, porcine RPE cells (e.g., GenVec), PMI-002, PLG-101(e.g., BiCentis®), PJ-34, PI3K conjugates (e.g., Semafore), PhotoPoint,Pharmaprojects No. 6526, pegaptanib sodium (e.g., SurModics®), PEDF ZFPTF, PEDF gene therapy (e.g., GenVec), PDS-1.0, PAN-90806, Opt-21,OPK-HVB-010, OPK-HVB-004, Ophthalmologicals (e.g., Cell NetwoRx),ophthalmic compounds (e.g., AstraZenca and Alcon), OcuXan, NTC-200,NT-502, NOVA-21012, Neurosolve®, neuroprotective (e.g., BDSI), MEDI-548,MCT-355, McEye®, LentiVue®, LYN-002, LX-213, lutetium texaphyrin (e.g.,Antrin®), LG-339 inhibitors (e.g., Lexicon), KDR kinase inhibitors(e.g., Merck), ISV-616, INDUS-815C, ICAM-1 aptamer (e.g., Eyetech),hedgehog antagonists (e.g., Opthalmo), GTx-822, GS-102, GranzymeB/VEGF®, gene therapy (e.g., EyeGate), GCS-100 analogue programme,FOV-RD-27, fibroblast growth factor (e.g., Ramot), fenretinide, F-200(e.g., Eos-200-F), Panzem SR®, ETX-6991, ETX-6201, EG-3306, Dz-13,disulfiram (e.g., ORA-102), Diclofenac (e.g., Ophthalmopharma), ACU-02,CLT-010, CLT-009, CLT-008, CLT-007, CLT-006, CLT-005, CLT-004, CLT-003(e.g., Chirovis®), CLT-001, Cethrin® (e.g., BA-210), celecoxib, CD91antagonist (e.g., Ophthalmophar), CB-42, BNC-4, bestrophin, batimastat,BA-1049, AVT-2, AVT-1, atu012, Apel programme (e.g., ApeX-2), anti-VEGF(e.g., Gryphon), AMD ZFPs (e.g., ToolGen), AMD therapy (e.g.,Optherion), AMD therapy (e.g., ItherX), dry AMD therapy (e.g., Opko),AMD therapy (e.g., CSL), AMD therapies (e.g., Pharmacopeia andAllergan), AMD therapeutic protein (e.g., ItherX), AMD RNAi therapy(e.g., BioMolecular Therapeutics), AM-1101, ALN-VEG01, AK-1003,AGN-211745, ACU-XSP-001 (e.g., Excellair®), ACU-HTR-028, ACU-HHY-011,ACT-MD (e.g., NewNeural), ABCA4 modulators (e.g., Active Pass), A36(e.g., Angstrom), 267268 (e.g., SB-267268), bevacizumab (e.g.,Avastin®), aflibercept (e.g., Eylea®), 131-I-TM-601, vandetanib (e.g.,Caprelsa®, Zactima®, Zictifa®), sunitinib malate (e.g., Sutene®,Sutent®), sorafenib (e.g., Nexavar®), pazopanib (e.g., Armala®,Patorma®, Votrient®), axitinib (e.g., Inlyta®), tivozanib, XL-647,RAF-265, pegdinetanib (e.g., Angiocept®), pazopanib, MGCD-265,icrucumab, foretinib, ENMD-2076, BMS-690514, regorafenib, ramucirumab,plitidepsin (e.g., Aplidin®), orantinib, nintedanib (e.g., Vargateft),motesanib, midostaurin, linifanib, telatinib, lenvatinib, elpamotide,dovitinib, cediranib (e.g., Recentin®), JI-101, cabozantinib, brivanib,apatinib, Angiozyme®, X-82, SSR-106462, rebastinib, PF-337210, IMC-3C5,CYC 116, AL-3818, VEGFR-2 inhibitor (e.g., AB Science), VEGF/rGel (e.g.,Clayton Biotechnologies), TLK-60596, TLK-60404, R84 antibody (e.g.,Peregrine), MG-516, FLT4 kinase inhibitors (e.g., Sareum), fit-4 kinaseinhibitors, Sareum, DCC-2618, CH-330331, XL-999, XL-820, vatalanib,SU-14813, semaxanib, KRN-633, CEP-7055, CEP-5214, ZK-CDK, ZK-261991,YM-359445, YM-231146, VEGFR-2 kinase inhibitors (e.g., Takeda), VEGFR-2kinase inhibitors (e.g., Hanmi), VEGFR-2 antagonist (e.g., Affymax),VEGF/rGel (e.g., Targa), VEGF-TK inhibitors (e.g., AstraZeneca),tyrosine kinase inhibitors (e.g., Abbott), tyrosine kinase inhibitors(e.g., Abbott), Tie-2 kinase inhibitors (e.g., GSK), SU-0879, SP-5.2,sorafenib bead (e.g., Nexavar® bead), SAR-131675, Ro-4383596, R-1530,Pharmaprojects No. 6059, OSI-930, OSI-817, OSI-632, MED-A300,L-000021649, KM-2550, kinase inhibitors (e.g., MethylGene), kinaseinhibitors (e.g., Amgen), Ki-8751, KDR kinase inhibitors (e.g.,Celltech), KDR kinase inhibitors (e.g., Merck), KDR kinase inhibitors(e.g., Amgen), KDR inhibitors (e.g., Abbott), KDR inhibitor (e.g.,LGLS), JNJ-17029259, IMC-1C11, Flt 3/4 anticancer (e.g., Sentinel),EG-3306, DP-2514, DCC-2157, CDP-791, CB-173, c-kit inhibitors (e.g.,Deciphera), BIW-8556, anticancers (e.g., Bracco and Dyax), anti-Flt-1MAbs (e.g., ImClone), AGN-211745, AEE-788, or AB-434. In certainembodiments, the additional pharmaceutical agent is a pharmaceuticalagent useful for treating and/or preventing dry eye, such ascyclosporine (Restasis®). In certain embodiments, the additionalpharmaceutical agent is a pharmaceutical agent useful for treatingand/or preventing cystoid macular edema (CME), such as an NSAID (e.g.,bromfenac (Bromday®)). In certain embodiments, the additionalpharmaceutical agent is a pharmaceutical agent useful for treatingand/or preventing diabetic macular edema (DME), such as ranibizumab(Lucentis®). In certain embodiments, the additional pharmaceutical agentis a pharmaceutical agent useful for treating and/or preventing uveitis,such as TobraDex® (0.1% dexamethasone/0.3% tobramycin), Zylet® (0.5%loteprednol etabonate/0.3% tobramycin)), triamcinolone acetonide(Trivaris® and Triesence®), fluocinolone acetonide (Retisert®), anddexamethasone (Ozurdex®). In certain embodiments, the additionalpharmaceutical agent is a pharmaceutical agent useful for treatingand/or preventing glaucoma, such as latanoprost (Xalatan®), bimatoprost(Lumigan®), travoprost (Travatan Z®), timolol (Timoptic®), brimonidinetartrate (Alphagan®), dorzolamide (Trusopt®), and pilocarpine (Isopto®).In certain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful for treating and/or preventing an ocularinflammatory disease (e.g., post-surgical inflammation), such assteroids (e.g., loteprednol etabonate (Lotemax®), difluprednate(Durezol®), prednisolone acetate (Pred Mild® and Omnipred®) and NSAIDs(e.g., bromfenac (Bromday®), nepafenac (Nevanac®), ketorolactromethamine (Acular LS®, Acuvail®, Toradol®, and Sprix®), diclofenac(Voltaren®, Aclonac®, and Cataflam®).

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The kits provided may comprise an inventive pharmaceutical compositionor compound and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of an inventive pharmaceutical composition or compound. Insome embodiments, the inventive pharmaceutical composition or compoundprovided in the first container and the second container are combined toform one unit dosage form.

Thus, in one aspect, provided are kits including a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, or prodrug thereof, or a pharmaceuticalcomposition thereof. In certain embodiments, the kits described hereinare useful for preventing and/or treating a disease described herein. Incertain embodiments, the kits described herein are useful for preventingand/or treating a disease associated with aberrant signaling of a growthfactor (e.g., VEGF) in a subject in need thereof. In certainembodiments, the kits described herein are useful for preventing and/ortreating a disease associated with abnormal angiogenesis in a subject inneed thereof. In certain embodiments, the kits described herein areuseful for preventing and/or treating proliferative diseases (e.g.,cancers, benign neoplasms, inflammatory diseases, autoimmune diseases)and/or ocular diseases (e.g., macular degeneration, glaucoma, diabeticretinopathy, retinoblastoma, edema, uveitis, dry eye, blepharitis, orpost-surgical inflammation). In certain embodiments, the kits describedherein are useful for inhibiting aberrant signaling of a growth factor(e.g., VEGF) in a subject or cell in need thereof. In certainembodiments, the kits described herein are useful for inhibitingabnormal angiogenesis in a subject in need thereof. In certainembodiments, the kits further include instructions for administering thecompound, or the pharmaceutically acceptable salt, solvate, hydrate,polymorph, co-crystal, tautomer, stereoisomer, isotopically labeledderivative, or prodrug, or the pharmaceutical composition thereof. Thekits may also include information as required by a regulatory agencysuch as the U.S. Food and Drug Administration (FDA). In certainembodiments, the information included in the kits is prescribinginformation. In certain embodiments, the kits and instructions providefor treating and/or preventing a disease described herein. In certainembodiments, the kits and instructions provide for preventing and/ortreating a disease associated with aberrant signaling of a growth factor(e.g., VEGF) in a subject in need thereof. In certain embodiments, thekits and instructions provide for preventing and/or treating a diseaseassociated with abnormal angiogenesis in a subject in need thereof. Incertain embodiments, the kits and instructions provide for inhibitingaberrant signaling of a growth factor (e.g., VEGF) in a subject or cellin need thereof. In certain embodiments, the kits and instructionsprovide for inhibiting abnormal angiogenesis in a subject in needthereof. The kit of the invention may include one or more additionalpharmaceutical agents described herein as a separate composition.

Also provided by the present invention are particles that may penetratemucus, pharmaceutical compositions thereof, kits, and methods of usingand preparing the particles, and pharmaceutical compositions thereof.The pharmaceutical compositions, kits, and methods may involve modifyingthe surface coatings of particles, such as particles of pharmaceuticalagents that have a low aqueous solubility. Such pharmaceuticalcompositions, kits, and methods can be used to achieve efficienttransport of particles comprising the inventive compounds through mucusbarriers in a subject.

In certain embodiments, the compounds, particles, pharmaceuticalcompositions, kits, and methods of the invention are useful forapplications in the eye, such as treating and/or preventing an oculardisease (e.g., macular degeneration, dry eye syndrome, uveitis, allergicconjunctivitis, glaucoma, and rosacea).

The particles (e.g., nanoparticles and microparticles) of the inventioncomprise a compound of the invention. The particles of the inventionalso include a surface-altering agent that modifies the surface of theparticles to reduce the adhesion of the particles to mucus and/or tofacilitate penetration of the particles through mucus.

The present invention also provides pharmaceutical compositionscomprising the inventive particles. In certain embodiments, thepharmaceutical compositions of the invention can be topicallyadministered to the eye of a subject. Topical pharmaceuticalcompositions are advantageous over pharmaceutical compositions that areadministered by injection or orally.

Particles

The present invention also provides pharmaceutical compositionscomprising a plurality of particles of the invention, which may bemucus-penetrating and may include a pharmaceutical agent (e.g., acompound of the invention). The inventive pharmaceutical compositionsmay be useful to deliver the pharmaceutical agent to the eye of asubject and to treat and/or prevent an ocular disease of the subject.

Without wishing to be bound by theory, it is believed that conventionalparticles (CPs, e.g., non-MPPs) are trapped in the mucus layer (e.g.,eye mucin) and are readily cleared from the subject. Thus, theconventional particles may be cleared before the drugs contained in theparticles can be transported to target tissue or site (e.g., bydiffusion or other mechanisms). In contrast, the particles of theinvention (e.g., MPPs) may avoid adhesion to secreted mucins, therebyprolonging particle retention and sustaining drug release.

In some embodiments, once a particle is successfully transported acrossa mucosal barrier (e.g., mucus or a mucosal membrane) in a subject,further interactions between the particle in the subject may take place.Interactions may take place, in some instances, through the coatingand/or the core, and may involve, for example, the exchange of materials(e.g., pharmaceutical agents, therapeutic agents, proteins, peptides,polypeptides, nucleic acids, nutrients, e.g.) from the one or morecomponents of the subject to the particle and/or from the particle tothe one or more components of the subject. For example, in someembodiments in which the core is formed of or comprises a pharmaceuticalagent, the breakdown, release and/or transport of the pharmaceuticalagent from the particle can lead to certain beneficial and/ortherapeutic effects in the subject. As such, the particles describedherein can be used for the diagnosis, prevention, treatment ormanagement of certain diseases or bodily conditions.

In some embodiments, the particles of the invention have a core-shelltype configuration. The core may comprise any suitable material such asa solid pharmaceutical agent or a salt thereof having a relatively lowaqueous solubility, a polymeric carrier, a lipid, and/or a protein. Thecore may also comprise a gel or a liquid. The core may be coated with acoating or shell comprising a surface-altering agent that facilitatesmobility of the particle in mucus. As described in more detail below,the surface-altering agent may comprise a polymer (e.g., a synthetic ora natural polymer) having pendant hydroxyl groups on the backbone of thepolymer. The molecular weight and/or degree of hydrolysis of the polymermay be chosen to impart certain transport characteristics to theparticles, such as increased transport through mucus. In certainembodiments, the surface-altering agent may comprise a triblockcopolymer comprising a (hydrophilic block)-(hydrophobicblock)-(hydrophilic block) configuration. The molecular weights of eachone of the blocks may be chosen to impart certain transportcharacteristics to the particles, such as increased transport throughmucus. In some embodiments, at least one particle of the inventionincludes a core and a coating surrounding the core. A particle includinga core and a coating on the core is referred to as a “coated particle.”In certain embodiments, at least one particle of the invention includesa core but not a coating on the core. A particle including a core butnot a coating on the core is referred to as an “uncoated particle.”

In some embodiments, the compositions and methods involve the use ofpoloxamers that aid particle transport in mucus. Poloxamers aretypically nonionic triblock copolymers comprising a central hydrophobicblock (e.g., a poly(propylene oxide) block) flanked by two hydrophilicblocks (e.g., poly(ethylene oxide) blocks). Poloxamers have the tradename Pluronic®, examples of which are provided below

In certain embodiments, the compositions and methods involve the use ofpolysorbates that aid particle transport in mucus. Polysorbates aretypically derived from PEGylated sorbitan (a derivative of sorbitol)esterified with fatty acids. Common brand names for polysorbates includeTween®, Alkest®, Canarcel®. Examples of polysorbates includepolyoxyethylene sorbitan monooleate (e.g., Tween 80®), polyoxyethylenesorbitan monostearate (e.g., Tween 60®), polyoxyethylene sorbitanmonopalmitate (e.g., Tween 40®), and polyoxyethylene sorbitanmonolaurate (e.g., Tween 20®).

In some embodiments, a substantial portion of the core is formed of oneor more solid pharmaceutical agents (e.g., a compound of the invention)that can lead to certain beneficial and/or therapeutic effects. The coremay be, for example, a nanocrystal (i.e., a nanocrystalline particle) ofa pharmaceutical agent. In certain embodiments, the core includes apolymeric carrier, optionally with one or more pharmaceutical agentsencapsulated or otherwise associated with the core. In certainembodiments, the core includes a lipid, protein, gel, liquid, and/oranother suitable material to be delivered to a subject. The coreincludes a surface to which one or more surface-altering agents can beattached. In some embodiments, the core is surrounded by coating, whichincludes an inner surface and an outer surface. The coating may beformed, at least in part, of one or more surface-altering agents, suchas a polymer (e.g., a block copolymer and/or a polymer having pendanthydroxyl groups), which may associate with the surface of the core. Thesurface-altering agent may be associated with the core particle by, forexample, being covalently attached to the core particle, non-covalentlyattached to the core particle, adsorbed to the core, or attached to thecore through ionic interactions, hydrophobic and/or hydrophilicinteractions, electrostatic interactions, van der Waals interactions, orcombinations thereof. In some embodiments, the surface-altering agents,or portions thereof, are chosen to facilitate transport of the particlethrough or into a mucosal barrier (e.g., mucus or a mucosal membrane).In certain embodiments described herein, one or more surface-alteringagents are oriented in a particular configuration in the coating. Insome embodiments, in which a surface-altering agent is a triblockcopolymer, such as a triblock copolymer having a (hydrophilicblock)-(hydrophobic block)-(hydrophilic block) configuration, ahydrophobic block may be oriented towards the surface of the core, andhydrophilic blocks may be oriented away from the core surface (e.g.,towards the exterior of the particle). The hydrophilic blocks may havecharacteristics that facilitate transport of the particle through amucosal barrier, as described in more detail below.

In some embodiments the core may be formed of solid materials havingvarious aqueous solubilities (i.e., a solubility in water, optionallywith one or more buffers), and/or various solubilities in the solutionin which the solid material is being coated with a surface-alteringagent. For example, the solid material may have an aqueous solubility(or a solubility in a coating solution) of less than or equal to about 5mg/mL, less than or equal to about 2 mg/mL, less than or equal to about1 mg/mL, less than or equal to about 0.5 mg/mL, less than or equal toabout 0.1 mg/mL, less than or equal to about 0.05 mg/mL, less than orequal to about 0.01 mg/mL, less than or equal to about 1 g/mL, less thanor equal to about 0.1 μg/mL, less than or equal to about 0.01 μg/mL,less than or equal to about 1 ng/mL, less than or equal to about 0.1ng/mL, or less than or equal to about 0.01 ng/mL at 25° C. In someembodiments, the solid material may have an aqueous solubility (or asolubility in a coating solution) of at least about 1 pg/mL, at leastabout 10 pg/mL, at least about 0.1 ng/mL, at least about 1 ng/mL, atleast about 10 ng/mL, at least about 0.1 jag/mL, at least about 1 g/mL,at least about 5 μg/mL, at least about 0.01 mg/mL, at least about 0.05mg/mL, at least about 0.1 mg/mL, at least about 0.5 mg/mL, at leastabout 1.0 mg/mL, at least about 2 mg/mL. Combinations of the above-notedranges are possible (e.g., an aqueous solubility or a solubility in acoating solution of at least about 10 pg/mL and less than or equal toabout 1 mg/mL). Other ranges are also possible. The solid material mayhave these or other ranges of aqueous solubilities at any pointthroughout the pH range (e.g., from pH 1 to pH 14).

In embodiments in which the core comprises an inorganic material (e.g.,for use as imaging agents), the inorganic material may include, forexample, a metal (e.g., Ag, Au, Pt, Fe, Cr, Co, Ni, Cu, Zn, and othertransition metals), a semiconductor (e.g., silicon, silicon compoundsand alloys, cadmium selenide, cadmium sulfide, indium arsenide, andindium phosphide), or an insulator (e.g., ceramics such as siliconoxide). The inorganic material may be present in the core in anysuitable amount, e.g., at least about 1 wt %, at least about 5 wt %, atleast about 10 wt %, at least about 20 wt %, at least about 30 wt %, atleast about 40 wt %, at least about 50 wt %, at least about 75 wt %, atleast about 90 wt %, or at least about 99 wt %. In one embodiment, thecore is formed of 100 wt % inorganic material. In some cases, theinorganic material may be present in the core at less than or equal toabout 100 wt %, less than or equal to about 90 wt %, less than or equalto about 80 wt %, less than or equal to about 70 wt %, less than orequal to about 60 wt %, less than or equal to about 50 wt %, less thanor equal to about 40 wt %, less than or equal to about 30 wt %, lessthan or equal to about 20 wt %, less than or equal to about 10 wt %,less than or equal to about 5 wt %, less than or equal to about 2 wt %,or less than or equal to about 1 wt %. Combinations of theabove-referenced ranges are also possible (e.g., present in an amount ofat least about 1 wt % and less than or equal to about 20 wt %). Otherranges are also possible.

The core of a particle described herein may include a mixture of morethan one polymer. In some embodiments, the core, or at least a portionof the core, includes a mixture of a first polymer and a second polymer.In certain embodiments, the first polymer is a polymer described herein.In certain embodiments, the first polymer is a relatively hydrophobicpolymer (e.g., a polymer having a higher hydrophobicity than the secondpolymer). In certain embodiments, the first polymer is not a polyalkylether. In certain embodiments, the first polymer is polylactide (PLA),e.g., 100DL7A MW108K. In certain embodiments, the first polymer ispolylactide-co-glycolide (PLGA), e.g., PLGA1A MW4K. In otherembodiments, however, the first polymer may be a relatively hydrophilicpolymer (e.g., a polymer having a higher hydrophilicity than the secondpolymer).

In certain embodiments, the second polymer is a block copolymerdescribed herein (e.g., a diblock copolymer or a triblock copolymer). Incertain embodiments, the second polymer is a diblock copolymer includinga relatively hydrophilic block (e.g., a polyalkyl ether block) and arelatively hydrophobic block (e.g., a non-(polyalkyl ether) block). Incertain embodiments, the polyalkyl ether block of the second polymer isPEG (e.g., PEG2K or PEG5K). In certain embodiments, the non-(polyalkylether) block of the second polymer is PLA (e.g., 100DL9K, 100DL30, or100DL95). In certain embodiments, the non-(polyalkyl ether) block of thesecond polymer is PLGA (e.g., 8515PLGA54K, 7525PLGA15K, or 5050PLGA18K).In certain embodiments, the second polymer is 100DL9K-co-PEG2K. Incertain embodiments, the second polymer is 8515PLGA54K-co-PEG2K.

It should be appreciated that while “first” and “second” polymers aredescribed, in some embodiments, a particle or core described herein mayinclude only one such polymer. Additionally, while specific examples offirst and second polymers are provided, it should be appreciated thatother polymers, such as the polymers listed herein, can be used as firstor second polymers.

The first polymer and the relatively hydrophobic block of the secondpolymer may be the same or different polymer. In some cases, therelatively hydrophilic block of the second polymer is present primarilyat or on the surface of the core that includes the first and secondpolymers. For instance, the relatively hydrophilic block of the secondpolymer may act as a surface-altering agent as described herein. In somecases, the relatively hydrophobic block of the second polymer and thefirst polymer are present primarily inside the surface of the core thatincludes the first and second polymers.

The relatively hydrophilic block (e.g., a polyalkyl ether block, such asPEG block) of the second polymer may have any suitable molecular weight.In certain embodiments, the molecular weight of the relativelyhydrophilic block of the second polymer is at least about 0.1 kDa, atleast about 0.2 kDa, at least about 0.5 kDa, at least about 1 kDa, atleast about 1.5 kDa, at least about 2 kDa, at least about 2.5 kDa, atleast about 3 kDa, at least about 4 kDa, at least about 5 kDa, at leastabout 6 kDa, at least about 8 kDa, at least about 10 kDa, at least about20 kDa, at least about 50 kDa, at least about 100 kDa, or at least about300 kDa. In certain embodiments, the molecular weight of the relativelyhydrophilic block of the second polymer is less than or equal to about300 kDa, less than or equal to about 100 kDa, less than or equal toabout 50 kDa, less than or equal to about 20 kDa, less than or equal toabout 10 kDa, less than or equal to about 8 kDa, less than or equal toabout 6 kDa, at least about 5 kDa, less than or equal to about 4 kDa,less than or equal to about 3 kDa, less than or equal to about 2.5 kDa,less than or equal to about 2 kDa, less than or equal to about 1.5 kDa,less than or equal to about 1 kDa, less than or equal to about 0.5 kDa,less than or equal to about 0.2 kDa, or less than or equal to about 0.1kDa. Combinations of the above-mentioned ranges are also possible (e.g.,at least about 0.5 kDa and less than or equal to about 10 kDa). Otherranges are also possible. In certain embodiments, the molecular weightof the relatively hydrophilic block of the second polymer is about 2kDa. In certain embodiments, the molecular weight of the relativelyhydrophilic block of the second polymer is about 5 kDa.

The relatively hydrophobic block (e.g., a non-(polyalkyl ether) block,such as PLGA or PLA block) of the second polymer may have any suitablemolecular weight. In certain embodiments, the relatively hydrophobicblock of the second polymer is relatively short in length and/or low inmolecular weight. In certain embodiments, the molecular weight of therelatively hydrophobic block of the second polymer is less than or equalto about 300 kDa, less than or equal to about 100 kDa, less than orequal to about 80 kDa, less than or equal to about 60 kDa, less than orequal to about 54 kDa, less than or equal to about 50 kDa, less than orequal to about 40 kDa, less than or equal to about 30 kDa, less than orequal to about 20 kDa, less than or equal to about 15 kDa less than orequal to about 10 kDa, less than or equal to about 5 kDa, less than orequal to about 2 kDa, or less than or equal to about 1 kDa. In certainembodiments, the molecular weight of the PLGA or PLA block of the secondpolymer is at least about 0.1 kDa, at least about 0.3 kDa, at leastabout 1 kDa, at least about 2 kDa, at least about 4 kDa, at least about6 kDa, at least about 7 kDa, at least about 8 kDa, at least about 9 kDa,at least about 10 kDa, at least about 12 kDa, at least about 15 kDa, atleast about 20 kDa, at least about 30 kDa, at least about 50 kDa, or atleast about 100 kDa. Combinations of the above-mentioned ranges are alsopossible (e.g., less than or equal to about 20 kDa and at least about 1kDa). Other ranges are also possible. In certain embodiments, themolecular weight of the relatively hydrophobic block of the secondpolymer is about 9 kDa.

The relatively hydrophilic block (e.g., a polyalkyl ether block, such asPEG block) of the second polymer may be present in any suitable amountor density at or on the surface of a core described herein. In certainembodiments, the PEG block of the second polymer is present at or on thesurface of the core at at least about 0.001, at least about 0.003, atleast about 0.03, at least about 0.1 at least about 0.15, at least about0.18, at least about 0.2, at least about 0.3, at least about 0.5, atleast about 1, at least about 3, at least about 30, or at least about100 PEG chains per nm² of the surface area of the core. In certainembodiments, the PEG block of the second polymer is present at or on thesurface of the core at less than or equal to about 100, less than orequal to about 30, less than or equal to about 10, less than or equal toabout 3, less than or equal to about 1, less than or equal to about 0.5,less than or equal to about 0.3, less than or equal to about 0.2, lessthan or equal to about 0.18, less than or equal to about 0.15, less thanor equal to about 0.1, less than or equal to about 0.03, less than orequal to about 0.01, less than or equal to about 0.003, or less than orequal to about 0.001 PEG chains per nm² of the surface area of the core.Combinations of the above-mentioned ranges are also possible (e.g., atleast about 0.03 and less than or equal to about 1 PEG chains per nm² ofthe surface area of the core). Other ranges are also possible. Incertain embodiments, the PEG block of the second polymer is present ator on the surface of the core at at least about 0.18 PEG chains per nm²of the surface area of the core.

The relatively hydrophilic block (e.g., a polyalkyl ether block, such asPEG block) of the second polymer may be present in any suitable amountin a particle or core described herein. In certain embodiments, therelatively hydrophilic block of the second polymer is present in thecore at less than or equal to about less than or equal to about 90 wt %,less than or equal to about 80 wt %, less than or equal to about 70 wt%, less than or equal to about 60 wt %, less than or equal to about 50wt %, less than or equal to about 40 wt %, less than or equal to about30 wt %, less than or equal to about 20 wt %, less than or equal toabout 10 wt %, less than or equal to about 5 wt %, less than or equal toabout 4 wt %, less than or equal to about 3 wt %, less than or equal toabout 2 wt %, less than or equal to about 1 wt %, less than or equal toabout 0.5 wt %, less than or equal to about 0.2 wt %, less than or equalto about 0.1 wt %, less than or equal to about 0.05 wt %, less than orequal to about 0.02 wt %, or less than or equal to about 0.01 wt % ofthe particle or core. In certain embodiments, the relatively hydrophilicblock of the second polymer is present in the core at at least about0.01 wt %, at least about 0.02 wt %, at least about 0.05 wt %, at leastabout 0.1 wt %, at least about 0.2 wt %, at least about 0.5 wt %, atleast about 1 wt %, at least about 2 wt %, at least about 3 wt %, atleast about 4 wt %, at least about 5 wt %, at least about 10 wt %, atleast about 20 wt %, at least about 30 wt %, at least about 40 wt %, atleast about 50 wt %, at least about 60 wt %, at least about 70 wt %, atleast about 80 wt %, or at least about 90 wt % of the particle or core.Combinations of the above-mentioned ranges are also possible (e.g., lessthan or equal to about 10 wt % and at least about 0.5 wt % of theparticle or core). Other ranges are also possible. In certainembodiments, the relatively hydrophilic block of the second polymer ispresent at less than or equal to about 3 wt % of the particle or core.

The relatively hydrophilic block (e.g., a polyalkyl ether block, such asPEG block) and the relatively hydrophobic block (e.g., a non-(polyalkylether) block, such as PLGA or PLA block) of the second polymer may bepresent in the core in any suitable ratio. In certain embodiments, theratio of the relatively hydrophilic block to relatively hydrophobicblock of the second polymers is at least about 1:99, at least about10:90, at least about 20:80, at least about 30:70, at least about 40:60,at least about 50:50, at least about 60:40, at least about 70:30, atleast about 80:20, at least about 90:10, or at least about 99:1 w/w. Incertain embodiments, the ratio of the relatively hydrophilic block torelatively hydrophobic block is less than or equal to about 99:1, lessthan or equal to about 90:10, less than or equal to about 80:20, lessthan or equal to about 70:30, less than or equal to about 60:40, lessthan or equal to about 50:50, less than or equal to about 40:60, lessthan or equal to about 30:70, less than or equal to about 20:80, lessthan or equal to about 10:90, or less than or equal to about 1:99 w/w.Combinations of the above-mentioned ranges are also possible (e.g.,greater than about 70:30 and less than or equal to about 90:10 w/w).Other ranges are also possible. In certain embodiments, the ratio of therelatively hydrophilic block to relatively hydrophobic block is about20:80 w/w.

The first polymer (e.g., PLA or PLGA) and the second polymer (e.g.,PLA-co-PEG or PLGA-co-PEG) may be present in the particle or core in anysuitable ratio. In certain embodiments, the ratio of the first polymerto second polymer in the particle or core is at least about 1:99, atleast about 10:90, at least about 20:80, at least about 30:70, at leastabout 40:60, at least about 50:50, at least about 60:40, at least about65:35, at least about 70:30, at least about 75:25, at least about 80:20,at least about 85:15, at least about 90:10, at least about 95:5, or atleast about 99:1 w/w. In certain embodiments, the ratio of the firstpolymer to second polymer in the particle or core is less than or equalto about 99:1, less than or equal to about 95:5, less than or equal toabout 90:10, less than or equal to about 85:15, less than or equal toabout 80:20, less than or equal to about 75:25, less than or equal toabout 70:30, less than or equal to about 65:35, less than or equal toabout 60:40, less than or equal to about 50:50, less than or equal toabout 40:60, less than or equal to about 30:70, less than or equal toabout 20:80, less than or equal to about 10:90, or less than or equal toabout 1:99 w/w. Combinations of the above-mentioned ranges are alsopossible (e.g., greater than about 70:30 and less than or equal to about90:10 w/w). Other ranges are also possible. In certain embodiments, theratio of the first polymer to second polymer in the particle or core isabout 70:30 w/w. In certain embodiments, the ratio of the first polymerto second polymer in the particle or core is about 80:20 w/w.

The particle or core comprising a mixture of the first polymer and thesecond polymer described herein may further include a coating describedherein. The coating may be at or on the surface of the particle (e.g.,the surface of the first polymer and/or the second polymer). In someembodiments, the coating includes a hydrophilic material. The coatingmay include one or more surface-altering agents described herein, suchas a polymer and/or a surfactant (e.g., a PVA, a poloxamer, apolysorbate (e.g., Tween 80®)).

It should be understood that components and configurations other thanthose described herein may be suitable for certain particles andpharmaceutical compositions, and that not all of the componentsdescribed are necessarily present in some embodiments.

In some embodiments, particles of the invention, when introduced into asubject, may interact with one or more components in the subject such asmucus, cells, tissues, organs, particles, fluids (e.g., blood),microorganisms, and portions or combinations thereof. In someembodiments, the coating of the inventive particle can be designed toinclude surface-altering agents or other components with properties thatallow favorable interactions (e.g., transport, binding, and adsorption)with one or more materials from the subject. For example, the coatingmay include surface-altering agents or other components having a certainhydrophilicity, hydrophobicity, surface charge, functional group,specificity for binding, and/or density to facilitate or reduceparticular interactions in the subject. One example is choosing ahydrophilicity, hydrophobicity, surface charge, functional group,specificity for binding, and/or density of one or more surface-alteringagents to reduce the physical and/or chemical interactions between theparticle and mucus of the subject, so as to enhance the mobility of theparticle through mucus. Other examples are described in more detailbelow.

In some embodiments, once a particle is successfully transported intoand/or across a mucosal barrier (e.g., mucus or a mucosal membrane) in asubject, further interactions between the particle and the subject maytake place. In some embodiments, in which the core comprises apharmaceutical agent or compound of the invention, the conversion,breakdown, release, and/or transport of the pharmaceutical agent fromthe particle can lead to certain beneficial and/or therapeutic effectsin the subject. Therefore, the particles of the invention can be usedfor the treatment and/or prevention of certain diseases.

Examples for the use of the particles of the invention are providedbelow in the context of being suitable for administration to a mucosalbarrier (e.g., mucus or a mucosal membrane) in a subject. It should beappreciated that while many of the embodiments herein are described inthis context, and in the context of providing a benefit for diseasesthat involve transport of materials across a mucosal barrier, theinvention is not limited as such, and the particles, pharmaceuticalcompositions, and kits of the invention may be used to treat and/orprevent other diseases.

In some embodiments, the pharmaceutical compositions of the inventioncomprise MPPs that include a compound of the invention and optionally atleast one additional pharmaceutical agent, each of which is associatedwith polymer carriers via encapsulation or other processes. In otherembodiments, the pharmaceutical compositions of the invention compriseMPPs without any polymeric carriers or with minimal use of polymericcarriers. Polymer-based MPPs may have one or more inherent limitationsin some embodiments. In particular, in light of drug deliveryapplications, these limitations may include one or more of thefollowing. A) Low drug encapsulation efficiency and low drug loading:encapsulation of drugs into polymeric particles is often inefficient, asgenerally less than 10% of the total amount of drug used getsencapsulated into particles during manufacturing; additionally, drugloadings above 50% are rarely achieved. B) Convenience of usage:pharmaceutical compositions based on drug-loaded polymeric particles, ingeneral, typically need to be stored as dry powder to avoid prematuredrug release and thus require either point-of-use re-constitution or asophisticated dosing device. C) Biocompatibility: accumulation of slowlydegrading polymer carriers following repeated dosing and their toxicityover the long term present a major concern for polymeric drug carriers.D) Chemical and physical stability: polymer degradation may compromisestability of encapsulated drugs. In many encapsulation processes, thedrug undergoes a transition from a solution phase to a solid phase,which is not well-controlled in terms of physical form of the emergingsolid phase (i.e., amorphous vs. crystalline vs. crystallinepolymorphs); this is a concern for multiple aspects of pharmaceuticalcomposition performance, including physical and chemical stability andrelease kinetics. E) Manufacturing complexity: manufacturing, especiallyscalability, of drug-loaded polymeric MPPs is a fairly complex processthat may involve multiple steps and a considerable amount of toxicorganic solvents. Therefore, by avoiding or minimizing the need toencapsulate pharmaceutical agents into polymeric carriers, certainlimitations of polymeric MPPs with respect to drug loading, convenienceof usage, biocompatibility, stability, and/or complexity ofmanufacturing, may be addressed.

It should be appreciated, however, that in other embodiments,pharmaceutical agents may be associated with polymer carriers viaencapsulation or other processes. Thus, the description provided hereinis not limited in this respect. For instance, despite theabove-mentioned drawbacks of certain mucus-penetrating particlesincluding a polymeric carrier, in certain embodiments such particles maybe preferred. For example, it may be preferable to use polymer carriersfor controlled release purposes and/or for encapsulating certainpharmaceutical agents that are difficult to formulate into particles. Assuch, in some embodiments described herein, particles that include apolymer carrier are described.

In some embodiments, the pharmaceutical compositions of the inventioninvolve the use of poly(vinyl alcohols) (PVAs) to aid particle transportin mucus. The pharmaceutical compositions may involve making MPPs orMPCs by, for example, an emulsification process in the presence ofspecific PVAs. In certain embodiments, the pharmaceutical compositionsand methods involve making MPPs or MPCs from pre-fabricated particles bynon-covalent coating with specific PVAs. In some embodiments, thepharmaceutical compositions and methods involve making MPPs in thepresence of specific PVAs without any polymeric carriers or with minimaluse of polymeric carriers. It should be appreciated, however, that inother embodiments, polymeric carriers can be used.

PVA is a water-soluble non-ionic synthetic polymer. Due to its surfaceactive properties, PVA is widely used in the food and drug industries asa stabilizing agent for emulsions and, in particular, to enableencapsulation of a wide variety of compounds by emulsificationtechniques. PVA has the “generally recognized as safe” (GRAS) statuswith the Food and Drug Administration (FDA), and has been used inauricular, intramuscular, intraocular, intravitreal, iontophoretic,ophthalmic, oral, topical, and transdermal drug products and/or drugdelivery systems.

In certain previous studies, many have described PVA as a mucoadhesivepolymer, suggesting that incorporating PVA in the particle formulationprocess leads to particles that are strongly mucoadhesive. Surprisingly,and contrary to the established opinion that PVA is a mucoadhesivepolymer, it is discovered that pharmaceutical compositions of theinvention utilizing specific PVA grades in fact aid particle transportin mucus and are not mucoadhesive in certain applications of theinvention. Specifically, MPPs can be prepared by tailoring the degree ofhydrolysis and/or molecular weight of the PVA, which was previouslyunknown. This discovery significantly broadens the arsenal of techniquesand ingredients applicable for manufacturing MPPs.

In other embodiments, the pharmaceutical compositions of the inventionand the methods of making the particles and pharmaceutical compositionsof the invention involve PVAs in conjunction with other polymers or donot involve PVAs at all. For example, PEG and/or Pluronics® (poloxamers)may be included in the pharmaceutical compositions of the invention andmethods of making the particles and pharmaceutical compositions of theinvention, in addition to or in replace of PVAs. Other polymers, such asthose described herein, may also be used.

Core of the Particles

A particle of the invention includes a core. The core of the inventiveparticles may be formed of any suitable material, such as an organicmaterial, inorganic material, polymer, lipid, protein, or combinationsthereof. In some embodiments, the core is a solid. The solid may be, forexample, a crystalline, semi-crystalline, or amorphous solid, such as acrystalline, semi-crystalline, or amorphous solid pharmaceutical agent(e.g., a compound of the invention), or a salt thereof. In certainembodiments, the core is a gel or liquid (e.g., an oil-in-water orwater-in-oil emulsion).

One or more pharmaceutical agents may be present in the core. Thepharmaceutical agent may be present in the core in any suitable amount,e.g., at least about 80 wt % and less than about 100 wt % of the core).Other ranges are also possible.

Particles that are formed by encapsulating pharmaceutical agents intopolymeric carriers typically have a low loading of the pharmaceuticalagent (e.g., less than about 50 wt % of the core of the particles). Incontrast, in certain embodiments, the loading of the pharmaceuticalagent in the core of the inventive particles is high (e.g., at leastabout 50 wt % of the core). A high drug loading is an advantage for drugdelivery, since a high drug loading often means that fewer numbers ofparticles may be needed to achieve a desired effect. As describedherein, in other embodiments in which a relatively high amount of apolymer or other material forms the core, the loading of thepharmaceutical agent in the core is low (e.g., less than about 50 wt %of the core).

The core may comprise a solid material having various aqueoussolubilities and/or various solubilities in a coating solution (asolution in which the solid material is being coated with asurface-altering agent). For example, the solid material may have anaqueous solubility (or a solubility in a coating solution) of at leastabout 10 pg/mL and less than about or equal to about 1 mg/mL). Otherranges are also possible. The solid material may have these or otherranges of aqueous solubilities at any point throughout the pH range(e.g., from pH 1 to pH 14).

In some embodiments, the core may be formed of a material within one ofthe ranges of solubilities classified by the U.S. PharmacopeiaConvention: e.g., very soluble: >1,000 mg/mL; freely soluble: 100-1,000mg/mL; soluble: 33-100 mg/mL; sparingly soluble: 10-33 mg/mL; slightlysoluble: 1-10 mg/mL; very slightly soluble: 0.1-1 mg/mL; and practicallyinsoluble: <0.1 mg/mL.

In certain embodiments, the core of the particles of the invention ishydrophobic. In certain embodiments, the core is substantiallyhydrophobic. In certain embodiments, the core is hydrophilic. In certainembodiments, the core is substantially hydrophilic.

In some embodiments, the core includes one or more organic materials,such as a synthetic polymer and/or natural polymer. Examples ofsynthetic polymers include non-degradable polymers (e.g.,polymethacrylate) and degradable polymers (e.g., polylactic acid andpolyglycolic acid), and copolymers thereof. Examples of natural polymersinclude hyaluronic acid, chitosan, and collagen. Other examples ofpolymers that may be suitable for portions of the core include thosesuitable for forming coatings on particles, as described herein. In somecases, the one or more polymers present in the core may be used toencapsulate or adsorb one or more pharmaceutical agents.

When a polymer is present in the core, the polymer may be present in thecore in any suitable amount, e.g., less than about 100 wt %, less thanabout 80 wt %, less than about 60 wt %, less than about 50 wt %, lessthan about 40 wt %, less than about 30 wt %, less than about 20 wt %,less than about 10 wt %, less than about 5 wt %, or less than about 1 wt%. In some cases, the polymer may be present in an amount of at leastabout 1 wt %, at least about 5 wt %, at least about 10 wt %, at leastabout 20 wt %, at least about 30 wt %, at least about 40 wt %, at leastabout 50 wt %, at least about 75 wt %, at least about 90 wt %, or atleast about 99 wt % in the core. Combinations of the above-referencedranges are also possible (e.g., present in an amount of at least about 1wt % and less than about 20 wt %). Other ranges are also possible. Insome embodiments, the core is substantially free of a polymericcomponent.

The core may have any suitable shape and/or size. For instance, the coremay be substantially spherical, non-spherical, oval, rod-shaped,pyramidal, cube-like, disk-shaped, wire-like, or irregularly shaped. Thecore may have a largest or smallest cross-sectional dimension of, forexample, less than about 10 μm, less than about 3 μm, less than about 1μm, less than about 500 nm, less than 400 nm, less than 300 nm, lessthan about 200 nm, less than about 100 nm, less than about 30 nm, orless than about 10 nm. In some cases, the core may have a largest orsmallest cross-sectional dimension of, for example, at least about 10nm, at least about 30 nm, at least about 100 nm, at least about 200 nm,at least about 300 nm, at least about 400 nm, at least about 500 nm, atleast about 1 μm, or at least about 3 μm. Combinations of theabove-referenced ranges are also possible (e.g., a largest or smallestcross-sectional dimension of at least about 30 nm and less than about500 nm). Other ranges are also possible. In some embodiments, the sizesof the cores formed by a process described herein have a Gaussian-typedistribution. Unless indicated otherwise, the measurements of theparticle sizes or core sizes refer to the smallest cross-sectionaldimension.

Techniques to determine sizes (e.g., smallest or largest cross-sectionaldimensions) of particles are known in the art. Examples of suitabletechniques include dynamic light scattering (DLS), transmission electronmicroscopy, scanning electron microscopy, electroresistance counting andlaser diffraction. Although many methods for determining sizes ofparticles are known, the sizes described herein (e.g., average particlesizes and thicknesses) refer to ones measured by DLS.

Coating of the Particles

A particle of the invention may include a coating. An inventive particleincluding a coating may be referred to as a coated particle of theinvention. An inventive particle not including a coating may be referredto as an uncoated particle of the invention. In some embodiments, thecoating is formed of one or more surface-altering agents or othermolecules disposed on the surface of the core. The particular chemicalmakeup and/or components of the coating and surface-altering agent(s)can be chosen so as to impart certain functionality to the particles,such as enhanced transport through mucosal barriers.

It should be understood that a coating which surrounds a core need notcompletely surround the core, although such embodiments may be possible.For example, the coating may surround at least about 10%, at least about30%, at least about 50%, at least about 70%, at least about 90%, or atleast about 99% of the surface area of a core. In some cases, thecoating substantially surrounds a core. In other cases, the coatingcompletely surrounds a core. In other embodiments, a coating surroundsless than about 100%, less than about 90%, less than about 70%, or lessthan about 50% of the surface area of a core. Combinations of theabove-referenced ranges are also possible (e.g., surrounding at least70% and less than 100% of the surface area of a core).

The material of the coating may be distributed evenly across a surfaceof the core in some cases, and unevenly in other cases. For example, thecoating may include portions (e.g., holes) that do not include anymaterial. If desired, the coating may be designed to allow penetrationand/or transport of certain molecules and components into or out of thecoating, but may prevent penetration and/or transport of other moleculesand components into or out of the coating. The ability of certainmolecules to penetrate and/or be transported into and/or across acoating may depend on, for example, the packing density of thesurface-altering agents forming the coating and the chemical andphysical properties of the components forming the coating. As describedherein, the coating may include one layer of material (i.e., amonolayer) or multilayers of materials. A single type or multiple typesof surface-altering agent may be present.

The coating of particles of the invention can have any suitablethickness. For example, the coating may have an average thickness of atleast about 1 nm, at least about 3 nm, at least about 10 nm, at leastabout 30 nm, at least about 100 nm, at least about 300 nm, at leastabout 1 μm, or at least about 3 m. In some cases, the average thicknessof the coating is less than about 3 m, less than about 1 μm, less thanabout 300 nm, less than about 100 nm, less than about 30 nm, less thanabout 10 nm, or less than about 3 nm. Combinations of theabove-referenced ranges are also possible (e.g., an average thickness ofat least about 1 nm and less than about 100 nm). Other ranges are alsopossible. For particles having multiple coatings, each coating may haveone of the thicknesses described herein.

The pharmaceutical compositions of the invention may allow for thecoating of the particles of the invention with hydrophilicsurface-altering moieties without requiring covalent association of thesurface-altering moieties to the surface of the core. In someembodiments, the core having a hydrophobic surface is coated with apolymer described herein, thereby causing a plurality ofsurface-altering moieties to be on the surface of the core withoutsubstantially altering the characteristics of the core itself. Forexample, the surface altering agent may be present on (e.g., adsorbedto) the outer surface of the core. In other embodiments, asurface-altering agent is covalently linked to the core.

In certain embodiments in which the surface-altering agent is adsorbedonto a surface of the core, the surface-altering agent may be inequilibrium with other molecules of the surface-altering agent insolution, optionally with other components (e.g., in a pharmaceuticalcomposition). In some cases, the adsorbed surface-altering agent may bepresent on the surface of the core at a density described herein. Thedensity may be an average density as the surface altering agent is inequilibrium with other components in solution.

The coating and/or surface-altering agent of the particles of theinvention may comprise any suitable material, such as a hydrophobicmaterial, a hydrophilic material, and/or an amphiphilic material. Insome embodiments, the coating includes a polymer. In certainembodiments, the polymer is a synthetic polymer (i.e., a polymer notproduced in nature). In other embodiments, the polymer is a naturalpolymer (e.g., a protein, polysaccharide, or rubber). In certainembodiments, the polymer is a surface active polymer. In certainembodiments, the polymer is a non-ionic polymer. In certain embodiments,the polymer is a linear synthetic non-ionic polymer. In certainembodiments, the polymer is a non-ionic block copolymer. The polymer maybe a copolymer. In certain embodiments, one repeat unit of the copolymeris relatively hydrophobic and another repeat unit of the copolymer isrelatively hydrophilic. The copolymer may be, for example, a diblock,triblock, alternating, or random copolymer. The polymer may be chargedor uncharged.

In some embodiments, the coating of the particles of the inventioncomprises a synthetic polymer having pendant hydroxyl groups on thebackbone of the polymer. Examples of the synthetic polymer are asdescribed herein. Without wishing to be bound by theory, a particleincluding a coating comprising a synthetic polymer having pendanthydroxyl groups on the backbone of the polymer may have reducedmucoadhesion as compared to a control particle due to, at least in part,the display of a plurality of hydroxyl groups on the particle surface.One possible mechanism for the reduced mucoadhesion is that the hydroxylgroups alter the microenvironment of the particle, for example, byordering water and other molecules in the particle/mucus environment. Anadditional or alternative possible mechanism is that the hydroxyl groupsshield the adhesive domains of the mucin fibers, thereby reducingparticle adhesion and speeding up particle transport.

Moreover, the ability of a particle coated with a synthetic polymerhaving pendant hydroxyl groups on the backbone of the polymer to bemucus penetrating may also depend, at least in part, on the degree ofhydrolysis of the polymer. In some embodiments, the hydrophobic portionsof the polymer (e.g., portions of the polymer that are not hydrolyzed)allow the polymer to be adhered to the surface of the core (e.g., in thecase that the surface of the core is hydrophobic), thus allowing for astrong association between the core and polymer. Surprisingly, it hasbeen found that, in some embodiments involving PVA as thesurface-altering agent, too high of a degree of hydrolysis does notallow for sufficient adhesion between the PVA and the core (e.g., in thecase of the core being hydrophobic), and thus, the particles coated withsuch a polymer generally do not exhibit sufficient reduced mucoadhesion.In some embodiments, too low of a degree of hydrolysis does not enhanceparticle transport in mucus, perhaps due to the lower amounts ofhydroxyl groups available for altering the microenvironment of theparticle and/or shielding the adhesive domains of the mucin fibers.

A synthetic polymer having pendant hydroxyl groups on the backbone ofthe polymer may have any suitable degree of hydrolysis (and, therefore,varying amounts of hydroxyl groups). The appropriate level of hydrolysismay depend on additional factors, such as the molecular weight of thepolymer, the pharmaceutical composition of the core, and thehydrophobicity of the core. In some embodiments, the synthetic polymeris at least about 30% hydrolyzed, at least about 40% hydrolyzed, atleast about 50% hydrolyzed, at least about 60% hydrolyzed, at leastabout 70% hydrolyzed, at least about 80% hydrolyzed, at least about 90%hydrolyzed, or at least about 95% hydrolyzed. In some embodiments, thesynthetic polymer is less than about 100% hydrolyzed, less than about95% hydrolyzed, less than about 90% hydrolyzed, less than about 80%hydrolyzed, less than about 70% hydrolyzed, or less than about 60%hydrolyzed. Combinations of the above-mentioned ranges are also possible(e.g., a synthetic polymer that is at least about 80% and less thanabout 95% hydrolyzed). Other ranges are also possible.

The molecular weight of the synthetic polymer described herein (e.g.,one having pendant hydroxyl groups on the backbone of the polymer) maybe selected so as to reduce the mucoadhesion of a core and to ensuresufficient association of the polymer with the core. In certainembodiments, the molecular weight of the synthetic polymer is at leastabout 1 kDa, at least about 2 kDa, at least about 5 kDa, at least about8 kDa, at least about 9 kDa, at least about 10 kDa, at least about 12kDa, at least about 15 kDa at least about 20 kDa, at least about 25 kDa,at least about 30 kDa, at least about 40 kDa, at least about 50 kDa, atleast about 60 kDa, at least about 70 kDa, at least about 80 kDa, atleast about 90 kDa, at least about 100 kDa at least about 110 kDa, atleast about 120 kDa, at least about 130 kDa, at least about 140 kDa, atleast about 150 kDa, at least about 200 kDa, at least about 500 kDa, orat least about 1000 kDa. In some embodiments, the molecular weight ofthe synthetic polymer is less than about 1000 kDa, less than about 500kDa, less than about 200 kDa, less than about, less than about 150 kDa,less than about 130 kDa, less than about 120 kDa, less than about 100kDa, less than about 85 kDa, less than about 70 kDa, less than about 65kDa, less than about 60 kDa, less than about 50 kDa, or less than about40 kDa, less than about 30 kDa, less than about 20 kDa, less than about15 kDa, or less than about 10 kDa. Combinations of the above-mentionedranges are also possible (e.g., a molecular weight of at least about 10kDa and less than about 30 kDa). The above-mentioned molecular weightranges can also be combined with the above-mentioned hydrolysis rangesto form suitable polymers.

In some embodiments, the synthetic polymer described herein is orcomprises PVA. In some embodiments, the synthetic polymer describedherein is or comprises partially hydrolyzed PVA. Partially hydrolyzedPVA includes two types of repeating units: vinyl alcohol units andresidual vinyl acetate units. The vinyl alcohol units are relativelyhydrophilic, and the vinyl acetate units are relatively hydrophobic. Insome instances, the sequence distribution of vinyl alcohol units andvinyl acetate units is blocky. For example, a series of vinyl alcoholunits may be followed by a series of vinyl acetate units, and followedby more vinyl alcohol units to form a polymer having a mixedblock-copolymer type arrangement, with units distributed in a blockymanner. In certain embodiments, the repeat units form a copolymer, e.g.,a diblock, triblock, alternating, or random copolymer. Polymers otherthan PVA may also have these configurations of hydrophilic units andhydrophobic units.

In some embodiments, the hydrophilic units of the synthetic polymerdescribed herein are substantially present at the outer surface of theparticles of the invention. For example, the hydrophilic units may forma majority of the outer surface of the coating and may help stabilizethe particles in an aqueous solution containing the particles. Thehydrophobic units may be substantially present in the interior of thecoating and/or at the surface of the core, e.g., to facilitateattachment of the coating to the core.

The molar fraction of the relatively hydrophilic units and therelatively hydrophobic units of the synthetic polymer described hereinmay be selected so as to reduce the mucoadhesion of a core and to ensuresufficient association of the polymer with the core, respectively. Asdescribed herein, the molar fraction of the hydrophobic units of thepolymer may be chosen such that adequate association of the polymer withthe core occurs, thereby increasing the likelihood that the polymerremains adhered to the core. The molar fraction of the relativelyhydrophilic units to the relatively hydrophobic units of the syntheticpolymer may be, for example, at least 0.5:1, at least 1:1, at least 2:1,at least 3:1, at least 5:1, at least 10:1, at least 20:1, at least 30:1,at least 50:1, or at least 100:1. In some embodiments, the molarfraction of the relatively hydrophilic units to the relativelyhydrophobic units of the synthetic polymer may be, for example, lessthan 100:1, less than 50:1, less than 30:1, less than 20:1, less than10:1, less than 5:1, less than 3:1, less than 2:1, or less than 1:1.Combinations of the above-referenced ranges are also possible (e.g., aratio of at least 1:1 and less than 50:1). Other ranges are alsopossible.

The molecular weight of the PVA polymer may also be tailored to increasethe effectiveness of the polymer to render particles mucus penetrating.Examples of PVA polymers having various molecular weights and degree ofhydrolysis are shown in Table 1.

TABLE 1 Molecular weight (MW) and degree of hydrolysis of variouspoly(vinyl alcohols) (PVAs).^(a) MW Hydrolysis degree PVA (kDa) (%) 2K75 2 75-79 9K80  9-10 80 13K87 13-23 87-89 13K98 13-23 98 31K87 31-5087-89 31K98 31-50 98-99 57K86 57-60 86-89 85K87  85-124 87-89 85K99 85-124  99+ 95K95  95 95 105K80 104 80 130K87 130 87-89 ^(a)The valuesof the molecular weight and hydrolysis degree of the PVAs were providedby the manufacturers of the PVAs.

In certain embodiments, the synthetic polymer is represented by theformula:

wherein:

u is an integer between 0 and 22730, inclusive; and

v is an integer between 0 and 11630, inclusive. In certain embodiments,u is an integer between 25 and 20600, inclusive. In some embodiments, vis an integer between 5 and 1100, inclusive. In certain embodiments, vis an integer between 0 and 400 inclusive or between 1 and 400inclusive. It is noted that u and v represent the total content of thevinyl alcohol and vinyl acetate repeat units in the polymer,respectively, rather than the block lengths.

The value of u may vary. In certain embodiments, n is at least 5, atleast 10, at least 20, at least 30, at least 50, at least 100, at least200, at least 300, at least 500, at least 800, at least 1000, at least1200, at least 1500, at least 1800, at least 2000, at least 2200, atleast 2400, at least 2600, at least 3000, at least 5000, at least 10000,at least 15000, at least 20000, or at least 25000. In some cases, n isless than or equal to 30000, less than or equal to 25000, less than orequal to 20000, less than or equal to 25000, less than or equal to20000, less than or equal to 15000, less than or equal to 10000, lessthan or equal to 5000, less than or equal to 3000, less than or equal to2800, less than or equal to 2400, less than or equal to 2000, less thanor equal to 1800, less than or equal to 1500, less than or equal to1200, less than or equal to 1000, less than or equal to 800, less thanor equal to 500, less than or equal to 300, less than or equal to 200,less than or equal to 100, or less than or equal to 50. Combinations ofthe above-referenced ranges are also possible (e.g., n being at least 50and less than or equal to 2000). Other ranges are also possible.

Similarly, the value of v may vary. For instance, in certainembodiments, m is at least 5, at least 10, at least 20, at least 30, atleast 50, at least 70, at least 100, at least 150, at least 200, atleast 250, at least 300, at least 350, at least 400, at least 500, atleast 800, at least 1000, at least 1200, at least 1500, at least 1800,at least 2000, at least 2200, at least 2400, at least 2600, at least3000, at least 5000, at least 10000, or at least 15000. In some cases, mis less than or equal to 15000, less than or equal to 10000, less thanor equal to 5000, less than or equal to 3000, less than or equal to2800, less than or equal to 2400, less than or equal to 2000, less thanor equal to 1800, less than or equal to 1500, less than or equal to1200, less than or equal to 1000, less than or equal to 800, less thanor equal to 500, less than or equal to 400, less than or equal to 350,less than or equal to 300, less than or equal to 250, less than or equalto 200, less than or equal to 150, less than or equal to 100, less thanor equal to 70, less than or equal to 50, less than or equal to 30, lessthan or equal to 20, or less than or equal to 10. Combinations of theabove-referenced ranges are also possible (e.g., m being at least 5 andless than or equal to 200). Other ranges are also possible.

In some embodiments, the particles of the invention include a coatingcomprising a block copolymer having a relatively hydrophilic block and arelatively hydrophobic block. In some cases, the hydrophilic blocks maybe substantially present at the outer surface of the particle. Forexample, the hydrophilic blocks may form a majority of the outer surfaceof the coating and may help stabilize the particle in an aqueoussolution containing the particle. The hydrophobic block may besubstantially present in the interior of the coating and/or at thesurface of the core, e.g., to facilitate attachment of the coating tothe core. In some embodiments, the coating comprises a surface-alteringagent including a triblock copolymer, wherein the triblock copolymercomprises a (hydrophilic block)-(hydrophobic block)-(hydrophilic block)configuration. Diblock copolymers having a (hydrophilicblock)-(hydrophobic block) configuration are also possible. Combinationsof block copolymers with other polymers suitable for use as coatings arealso possible. Non-linear block configurations are also possible such asin comb, brush, or star copolymers. In some embodiments, the relativelyhydrophilic block includes a synthetic polymer having pendant hydroxylgroups on the backbone of the polymer (e.g., PVA).

The molecular weight of the hydrophilic blocks and the hydrophobicblocks of the block copolymers described herein may be selected so as toreduce the mucoadhesion of a core and to ensure sufficient associationof the block copolymer with the core, respectively. The molecular weightof the hydrophobic block of the block copolymer may be chosen such thatadequate association of the block copolymer with the core occurs,thereby increasing the likelihood that the block copolymer remainsadhered to the core.

In certain embodiments, the molecular weight of each block of orcombined blocks of the (one or more) relatively hydrophobic blocks of ablock copolymer is at least about 0.5 kDa, at least about 1 kDa, atleast about 1.8 kDa, at least about 2 kDa, at least about 3 kDa, atleast about 4 kDa, at least about 5 kDa, at least about 6 kDa, at leastabout 10 kDa, at least about 12 kDa, at least about 15 kDa, at leastabout 20 kDa, or at least about 50 kDa, at least about 60 kDa, at leastabout 70 kDa, at least about 80 kDa, at least about 90 kDa, at leastabout 100 kDa at least about 110 kDa, at least about 120 kDa, at leastabout 130 kDa, at least about 140 kDa, at least about 150 kDa, at leastabout 200 kDa, at least about 500 kDa, or at least about 1000 kDa. Insome embodiments, the molecular weight of each block of or combinedblocks of the (one or more) relatively hydrophobic blocks is less thanabout 1000 kDa, less than about 500 kDa, less than about 200 kDa, lessthan about 150 kDa, less than about 140 kDa, less than about 130 kDa,less than about 120 kDa, less than about 110 kDa, less than about 100kDa, less than about 90 kDa, less than about 80 kDa, less than about 50kDa, less than about 20 kDa, less than about 15 kDa, less than about 13kDa, less than about 12 kDa, less than about 10 kDa, less than about 8kDa, or less than about 6 kDa. Combinations of the above-mentionedranges are also possible (e.g., at least about 3 kDa and less than about15 kDa). Other ranges are also possible.

In some embodiments, the combined relatively hydrophilic blocks (e.g.,two hydrophilic blocks of a triblock copolymer) of a block copolymer(e.g., a triblock copolymer) constitute at least about 10 wt %, at leastabout 20 wt %, at least about 30 wt %, at least about 40 wt %, at leastabout 50 wt %, at least about 60 wt %, or at least about 70 wt % of theblock copolymer. In some embodiments, the combined (one or more)relatively hydrophilic blocks of a block copolymer constitute less thanabout 90 wt %, less than about 80 wt %, less than about 60 wt %, lessthan about 50 wt %, or less than about 40 wt % of the block copolymer.Combinations of the above-referenced ranges are also possible (e.g., atleast about 30 wt % and less than about 70 wt %). Other ranges are alsopossible.

In some embodiments, the molecular weight of each block of or combinedblocks of the (one or more) relatively hydrophilic blocks of the blockcopolymer may be at least about 0.5 kDa, at least about 1 kDa, at leastabout 1.8 kDa, at least about 2 kDa, at least about 3 kDa, at leastabout 4 kDa, at least about 5 kDa, at least about 6 kDa, at least about10 kDa, at least about 12 kDa, at least about 15 kDa, at least about 20kDa, or at least about 50 kDa, at least about 60 kDa, at least about 70kDa, at least about 80 kDa, at least about 90 kDa, at least about 100kDa at least about 110 kDa, at least about 120 kDa, at least about 130kDa, at least about 140 kDa, at least about 150 kDa, at least about 200kDa, at least about 500 kDa, or at least about 1000 kDa. In certainembodiments, the molecular weight of each block of or combined blocks ofthe (one or more) relatively hydrophilic blocks is less than about 1000kDa, less than about 500 kDa, less than about 200 kDa, less than about150 kDa, less than about 140 kDa, less than about 130 kDa, less thanabout 120 kDa, less than about 110 kDa, less than about 100 kDa, lessthan about 90 kDa, less than about 80 kDa, less than about 50 kDa, lessthan about 20 kDa, less than about 15 kDa, less than about 13 kDa, lessthan about 12 kDa, less than about 10 kDa, less than about 8 kDa, lessthan about 6 kDa, less than about 5 kDa, less than about 3 kDa, lessthan about 2 kDa, or less than about 1 kDa. Combinations of theabove-mentioned ranges are also possible (e.g., at least about 0.5 kDaand less than about 3 kDa). Other ranges are also possible. Inembodiments in which two hydrophilic blocks flank a hydrophobic block,the molecular weights of the two hydrophilic blocks may be substantiallythe same or different.

In certain embodiments, the polymer of the surface-altering agentincludes a polyether portion. In certain embodiments, the polymerincludes a polyalkylether portion. In certain embodiments, the polymerincludes polyethylene glycol (PEG) tails. In certain embodiments, thepolymer includes a polypropylene glycol as the central portion. Incertain embodiments, the polymer includes polybutylene glycol as thecentral portion. In certain embodiments, the polymer includespolypentylene glycol as the central portion. In certain embodiments, thepolymer includes polyhexylene glycol as the central portion. In certainembodiments, the polymer is a triblock copolymer of one of the polymersdescribed herein. In some embodiments, a diblock or triblock copolymercomprises a synthetic polymer having pendant hydroxyl groups on thebackbone of the polymer (e.g., PVA) as one or more of the blocks (withvarying degrees of hydrolysis and varying molecular weights as describedherein). The synthetic polymer blocks may form the central portion orend portions of the block copolymer.

In certain embodiments, the polymer is a triblock copolymer of apolyalkyl ether (e.g., polyethylene glycol, polypropylene glycol) andanother polymer (e.g., a synthetic polymer having pendant hydroxylgroups on the backbone of the polymer (e.g., PVA). In certainembodiments, the polymer is a triblock copolymer of a polyalkyl etherand another polyalkyl ether. In certain embodiments, the polymer is atriblock copolymer of polyethylene glycol and another polyalkyl ether.In certain embodiments, the polymer is a triblock copolymer ofpolypropylene glycol and another polyalkyl ether. In certainembodiments, the polymer is a triblock copolymer with at least one unitof polyalkyl ether. In certain embodiments, the polymer is a triblockcopolymer of two different polyalkyl ethers. In certain embodiments, thepolymer is a triblock copolymer including a polyethylene glycol unit. Incertain embodiments, the polymer is a triblock copolymer including apolypropylene glycol unit. In certain embodiments, the polymer is atriblock copolymer of a more hydrophobic unit flanked by two morehydrophilic units. In certain embodiments, the hydrophilic units are thesame type of polymer. In some embodiments, the hydrophilic units includea synthetic polymer having pendant hydroxyl groups on the backbone ofthe polymer (e.g., PVA). In certain embodiments, the polymer includes apolypropylene glycol unit flanked by two more hydrophilic units. Incertain embodiments, the polymer includes two polyethylene glycol unitsflanking a more hydrophobic unit. In certain embodiments, the polymer isa triblock copolymer with a polypropylene glycol unit flanked by twopolyethylene glycol units. The molecular weights of the two blocksflanking the central block may be substantially the same or different.

In certain embodiments, the polymer is of the formula:

wherein each instance of p is independently an integer between 2 and1140, inclusive; and q is an integer between 2 and 1730, inclusive. Incertain embodiments, each instance of p is independently an integerbetween 10 and 170, inclusive. In certain embodiments, q is an integerbetween 5 and 70 inclusive. In certain embodiments, each instance of pis independently at least 2 times of q, 3 times of q, or 4 times of q.

In certain embodiments, the surface-altering agent comprises a(poly(ethylene glycol))-(poly(propylene oxide))-(poly(ethylene glycol))triblock copolymer (PEG-PPO-PEG triblock copolymer), present in thecoating alone or in combination with another polymer such as a syntheticpolymer having pendant hydroxyl groups on the backbone of the polymer(e.g., PVA). The molecular weights of the PEG and PPO segments of thePEG-PPO-PEG triblock copolymer may be selected so as to reduce themucoadhesion of the particles, as described herein. Without wishing tobe bound by any theory, the particles of the invention having a coatingcomprising a PEG-PPO-PEG triblock copolymer may have reducedmucoadhesion as compared to control particles due to, at least in part,the PEG segments on the surface of the particles of the invention. ThePPO segment may be adhered to the surface of the core (e.g., in the caseof the surface of the core being hydrophobic), thus allowing for astrong association between the core and the triblock copolymer. In someembodiments, the PEG-PPO-PEG triblock copolymer is associated with thecore through non-covalent interactions. For purposes of comparison, thecontrol particle may be, for example, a carboxylate-modified polystyreneparticle of similar size as the particle of the invention.

In certain embodiments, the surface-altering agent includes a polymercomprising a poloxamer, having the trade name Pluronic®. Pluronic®polymers that may be useful in the embodiments described herein include,but are not limited to, F127, F38, F108, F68, F77, F87, F88, F98, L101,L121, L31, L35, L43, L44, L61, L62, L64, L81, L92, N3, P103, P104, P105,P123, P65, P84, and P85. Examples of molecular weights of certainPluronic® polymers are shown in Table 2.

TABLE 2 Molecular weight (MW) of Pluronic ® polymers Average MW of thePEG MW of the MW PPO portion wt PEG portion Pluronic ® (Da) (Da) % (Da)F127 12000 3600 70 8400 L44 2000 1200 40 800 L81 2667 2400 10 267 L1013333 3000 10 333 P65 3600 1800 50 1800 L121 4000 3600 10 400 P103 42863000 30 1286 F38 4500 900 80 3600 P123 5143 3600 30 1543 P105 6000 300050 3000 F87 8000 2400 70 5600 F68 9000 1800 80 7200 P123 5750 4030 301730

Although other ranges may be possible, in some embodiments, thehydrophobic block of the PEG-PPO-PEG triblock copolymer has one of themolecular weights described above (e.g., at least about 3 kDa and lessthan about 15 kDa), and the combined hydrophilic blocks have a weightpercentage with respect to the polymer in one of the ranges describedabove (e.g., at least about 15 wt %, at least about 20 wt %, at leastabout 25 wt %, or at least about 30 wt %, and less than about 80 wt %).Certain Pluronic® polymers that fall within these criteria include, forexample, F127 (poloxamer 407), F108 (poloxamer 338), P105, and P103. Incertain embodiments, the particles of the invention including Pluronic®polymers that fall within these criteria are more mucus penetrating thanparticles including Pluronic® polymers that did not fall within thesecriteria. Materials that do not render the particles mucus penetratingalso include certain polymers such as polyvinylpyrrolidones(PVP/Kollidon), polyvinyl alcohol-polyethylene glycol graft-copolymer(Kollicoat IR), and hydroxypropyl methylcellulose (Methocel); oligomerssuch as solutol HS 15, Triton X100, tyloxapol, and cremophor RH 40; andsmall molecules such as Span 20, Span 80, octyl glucoside,cetytrimethylammonium bromide (CTAB), and sodium dodecyl sulfate (SDS).

Although much of the description herein may involve coatings comprisinga (hydrophilic block)-(hydrophobic block)-(hydrophilic block)configuration (e.g., a PEG-PPO-PEG triblock copolymer) or coatingscomprising a synthetic polymer having pendant hydroxyl groups, it shouldbe appreciated that the coatings are not limited to these configurationsand materials and that other configurations and materials are possible.

Furthermore, although many of the embodiments described herein involve asingle coating, in other embodiments, a particle may include more thanone coating (e.g., at least two, three, four, five, or more coatings),and each coating need not be formed of or comprise a mucus penetratingmaterial. In some embodiments, an intermediate coating (i.e., a coatingbetween the core surface and an outer coating) may include a polymerthat facilitates attachment of an outer coating to the core surface. Insome embodiments, an outer coating of a particle includes a polymercomprising a material that facilitates the transport of the particlethrough mucus.

The coating (e.g., an inner coating, intermediate coating, and/or outercoating) of the particles of the invention may include any suitablepolymer. In some embodiments, the polymer of the coating isbiocompatible and/or biodegradable. In some embodiments, the polymer ofthe coating comprises more than one type of polymer (e.g., at least two,three, four, five, or more types of polymers). In some embodiments, thepolymer of the coating is a random copolymer or a block copolymer (e.g.,a diblock or triblock copolymer) as described herein.

Non-limiting examples of suitable polymers of the coating may includepolyamines, polyethers, polyamides, polyesters, polycarbamates,polyureas, polycarbonates, polystyrenes, polyimides, polysulfones,polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines,polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles,and polyarylates. Non-limiting examples of specific polymers includepoly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA),poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid)(PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lacticacid-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA),poly(L-lactide) (PLLA), poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-caprolactone-co-glycolide),poly(D,L-lactide-co-PEO-co-D,L-lactide),poly(D,L-lactide-co-PPO-co-D,L-lactide), polyalkyl cyanoacrylate,polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA),poly(ethylene glycol), poly-L-glutamic acid, poly(hydroxy acids),polyanhydrides, polyorthoesters, poly(ester amides), polyamides,poly(ester ethers), polycarbonates, polyalkylenes such as polyethyleneand polypropylene, polyalkylene glycols such as poly(ethylene glycol)(PEG), polyalkylene terephthalates such as poly(ethylene terephthalate),polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such aspoly(vinyl acetate), polyvinyl halides such as poly(vinyl chloride)(PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS),polyurethanes, derivatized celluloses such as alkyl celluloses,hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocelluloses, hydroxypropylcellulose, carboxymethylcellulose, polymers ofacrylic acids, such as poly(methyl(meth)acrylate) (PMMA),poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate),poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate),poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate),poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropylacrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) (jointlyreferred to herein as “polyacrylic acids”), and copolymers and mixturesthereof, polydioxanone and its copolymers, polyhydroxyalkanoates,polypropylene fumarate), polyoxymethylene, poloxamers,poly(ortho)esters, poly(butyric acid), poly(valeric acid),poly(lactide-co-caprolactone), and trimethylene carbonate.

The molecular weight of the polymer of the coating may vary. In someembodiments, the molecular weight of the polymer of the coating is atleast about 0.5 kDa, at least about 1 kDa, at least about 1.8 kDa, atleast about 2 kDa, at least about 3 kDa, at least about 4 kDa, at leastabout 5 kDa, at least about 6 kDa, at least about 8 kDa, at least about10 kDa, at least about 12 kDa, at least about 15 kDa, at least about 20kDa, at least about 30 kDa, at least about 40 kDa, or at least about 50kDa. In some embodiments, the molecular weight of the polymer of thecoating is less than about 50 kDa, less than about 40 kDa, less thanabout 30 kDa, less than about 20 kDa, less than about 12 kDa, less thanabout 10 kDa, less than about 8 kDa, less than about 6 kDa, less thanabout 5 kDa, or less than about 4 kDa. Combinations of theabove-referenced ranges are possible (e.g., a molecular weight of atleast about 2 kDa and less than about 15 kDa). Other ranges are alsopossible. The molecular weight of the polymer of the coating may bedetermined using any known technique such as light-scattering and gelpermeation chromatography. Other methods are known in the art.

In certain embodiments, the molecular weight of the hydrophobic block ofthe triblock copolymer of the (hydrophilic block)-(hydrophobicblock)-(hydrophilic block) configuration is at least about 2 kDa, andthe two hydrophilic blocks constitute at least about 15 wt % of thetriblock copolymer.

In certain embodiments, a biocompatible polymer may be biodegradable,i.e., the polymer is able to degrade, chemically and/or biologically(e.g., by the cellular machinery or by hydrolysis), within aphysiological environment, such as within the body or when introduced tocells. For instance, the polymer may be one that hydrolyzesspontaneously upon exposure to water (e.g., within a subject), and/orthe polymer may degrade upon exposure to heat (e.g., at temperatures ofabout 37° C.). Degradation of a polymer may occur at varying rates,depending on the polymer or copolymer used. For example, the half-lifeof the polymer (the time at which 50% of the polymer is degraded intomonomers and/or other nonpolymeric moieties) may be on the order ofdays, weeks, months, or years, depending on the polymer. The polymer maybe biologically degraded, e.g., by enzymatic activity or cellularmachinery, in some cases, for example, through exposure to a lysozyme(e.g., having relatively low pH). In some cases, the polymer may bebroken down into monomers and/or other nonpolymeric moieties that cellscan either reuse or dispose of without significant toxic effect on thecells (i.e., fewer than about 20% of the cells are killed when thecomponents are added to cells in vitro). For example, polylactide may behydrolyzed to form lactic acid, polyglycolide may be hydrolyzed to formglycolic acid, etc.).

Examples of biodegradable polymers include, but are not limited to,poly(ethylene glycol)-poly(propylene oxide)-poly(ethylene glycol)triblock copolymers, poly(lactide) (or poly(lactic acid)),poly(glycolide) (or poly(glycolic acid)), poly(orthoesters),poly(caprolactones), polylysine, poly(ethylene imine), poly(acrylicacid), poly(urethanes), poly(anhydrides), poly(esters),poly(trimethylene carbonate), poly(ethyleneimine), poly(acrylic acid),poly(urethane), poly(beta amino esters) or the like, and copolymers orderivatives of these and/or other polymers, for example,poly(lactide-co-glycolide) (PLGA).

In certain embodiments, a polymer may biodegrade within a period that isacceptable in the desired application. In certain embodiments, such asin vivo therapy, such degradation occurs in a period usually less thanabout five years, one year, six months, three months, one month, fifteendays, five days, three days, or even one day or less (e.g., 1-4 hours,4-8 hours, 4-24 hours, 1-24 hours) on exposure to a physiologicalsolution with a pH between 6 and 8 having a temperature of between 25and 37° C. In other embodiments, the polymer degrades in a period ofbetween about one hour and several weeks, depending on the desiredapplication.

Although the particles of the invention, and the coating thereof, mayeach include polymers, in some embodiments, the particles of theinvention comprise a hydrophobic material that is not a polymer orpharmaceutical agent. Non-limiting examples of non-polymeric hydrophobicmaterials include, for example, metals, waxes, and organic materials(e.g., organic silanes and perfluorinated or fluorinated organicmaterials).

Particles with Reduced Mucoadhesion

Particles of the invention may have reduced mucoadhesiveness. A materialin need of increased diffusivity through mucus may be hydrophobic, mayinclude many hydrogen bond donors or acceptors, and/or may be highlycharged. In some cases, the material may include a crystalline oramorphous solid material. The material, which may serve as a core, maybe coated with a suitable polymer described herein, thereby forming aparticle with a plurality of surface-altering moieties on the surface,resulting in reduced mucoadhesion. Particles of the invention as havingreduced mucoadhesion may alternatively be characterized as havingincreased transport through mucus, being mobile in mucus, ormucus-penetrating (i.e., mucus-penetrating particles), meaning that theparticles are transported through mucus faster than a negative controlparticle. The negative control particle may be a particle that is knownto be mucoadhesive, e.g., an unmodified particle or core that is notcoated with a coating described herein, such as a 200 nm carboxylatedpolystyrene particle.

Particles of the invention may be adapted for delivery (e.g., oculardelivery) to mucus or a mucosal surface of a subject. The particles withsurface-altering moieties may be delivered to the mucosal surface of asubject, may pass through the mucosal barrier in the subject, and/orprolonged retention and/or increased uniform distribution of theparticles at mucosal surfaces, e.g., due to reduced mucoadhesion.

Furthermore, in some embodiments, the particles of the invention havingreduced mucoadhesion facilitate better distribution of the particles atthe surface of a tissue of a subject and/or have a prolonged presence atthe surface of the tissue, compared to particles that are moremucoadhesive. For example, a luminal space such as the gastrointestinaltract is surrounded by a mucus-coated surface. Mucoadhesive particlesdelivered to such a space are typically removed from the luminal spaceand from the mucus-coated surface by the subject's natural clearancemechanisms. The particles of the invention with reduced mucoadhesion mayremain in the luminal space for relatively longer periods compared tothe mucoadhesive particles. This prolonged presence may prevent orreduce clearance of the particles and/or may allow for betterdistribution of the particles on the surface of the tissue. Theprolonged presence may also affect the particle transport through theluminal space, e.g., the particles may distribute into the mucus layerand may reach the underlying epithelium.

In certain embodiments, the core of the particles of the inventioncoated with the polymer of the coating may pass through mucus or amucosal barrier in a subject, exhibit prolonged retention, and/orincrease uniform distribution of the particles at mucosal surfaces,e.g., such substances are cleared more slowly (e.g., at least about 2times, about 5 times, about 10 times, or even at least about 20 timesmore slowly) from a subject's body as compared to a negative controlparticle of the invention.

The mobility of the particles of the invention in mucus may becharacterized in, e.g., the relative velocity and/or diffusivity of theparticles. In certain embodiments, the particles of the invention havecertain relative velocity, <V_(mean)>_(rel), which is defined asfollows:

$\begin{matrix}{\left\langle V_{mean} \right\rangle_{rel} = \frac{\left\langle V_{mean} \right\rangle_{Sample} - \left\langle V_{mean} \right\rangle_{{Negative}\mspace{14mu}{control}}}{\left\langle V_{mean} \right\rangle_{{Positive}\mspace{14mu}{control}} - \left\langle V_{mean} \right\rangle_{{Negative}\mspace{14mu}{control}}}} & \left( {{Equation}\mspace{14mu} 1} \right)\end{matrix}$wherein:

<V_(mean)> is the ensemble average trajectory-mean velocity;

V_(mean) is the velocity of an individual particle averaged over itstrajectory;

the sample is the particle of interest;

the negative control is a 200 nm carboxylated polystyrene particle; andthe positive control is a 200 nm polystyrene particle densely PEGylatedwith 2-5 kDa PEG.

The relative velocity can be measured by a multiple particle trackingtechnique. For instance, a fluorescent microscope equipped with a CCDcamera can be used to capture 15 s movies at a temporal resolution of66.7 ms (15 frames/s) under 100× magnification from several areas withineach sample for each type of particles: sample, negative control, andpositive control. The sample, negative control, and positive control maybe fluorescent particles to observe tracking. Alternativelynon-fluorescent particles may be coated with a fluorescent molecule, afluorescently tagged surface agent, or a fluorescently tagged polymer.An advanced image processing software (e.g., Image Pro or MetaMorph) canbe used to measure individual trajectories of multiple particles over atime-scale of at least 3.335 s (50 frames).

In some embodiments, a particle described herein has a relative velocityof greater than or equal to about 0.3, greater than or equal to about0.4, greater than or equal to about 0.5, greater than or equal to about0.6, greater than or equal to about 0.7, greater than or equal to about0.8, greater than or equal to about 0.9, greater than or equal to about1.0, greater than or equal to about 1.1, greater than or equal to about1.2, greater than or equal to about 1.3, greater than or equal to about1.4, greater than or equal to about 1.5, greater than or equal to about1.6, greater than or equal to about 1.7, greater than or equal to about1.8, greater than or equal to about 1.9 or greater than or equal toabout 2.0 in mucus. In some embodiments, a particle described herein hasa relative velocity of less than or equal to about 10.0, less than orequal to about 8.0, less than or equal to about 6.0, less than or equalto about 4.0, less than or equal to about 3.0, less than or equal toabout 2.0, less than or equal to about 1.9, less than or equal to about1.8, less than or equal to about 1.7, less than or equal to about 1.6,less than or equal to about 1.5, less than or equal to about 1.4, lessthan or equal to about 1.3, less than or equal to about 1.2, less thanor equal to about 1.1, less than or equal to about 1.0, less than orequal to about 0.9, less than or equal to about 0.8, or less than orequal to about 1.7 in mucus. Combinations of the above-noted ranges arepossible (e.g., a relative velocity of greater than or equal to about0.5 and less than or equal to about 6.0). Other ranges are alsopossible. The mucus may be, for example, human cervicovaginal mucus.

In certain embodiments, a particle described herein can diffuse throughmucus or a mucosal barrier at a greater rate or diffusivity than acontrol particle or a corresponding particle (e.g., a correspondingparticle that is unmodified and/or is not coated with a coatingdescribed herein). In some cases, a particle described herein may passthrough mucus or a mucosal barrier at a rate of diffusivity that is atleast about 10 times, 20 times, 30 times, 50 times, 100 times, 200times, 500 times, 1000 times, 2000 times, 5000 times, 10000 times, ormore, higher than a control particle or a corresponding particle. Insome cases, a particle described herein may pass through mucus or amucosal barrier at a rate of diffusivity that is less than or equal toabout 10000 times higher, less than or equal to about 5000 times higher,less than or equal to about 2000 times higher, less than or equal toabout 1000 times higher, less than or equal to about 500 times higher,less than or equal to about 200 times higher, less than or equal toabout 100 times higher, less than or equal to about 50 times higher,less than or equal to about 30 times higher, less than or equal to about20 times higher, or less than or equal to about 10 times higher than acontrol particle or a corresponding particle. Combinations of theabove-referenced ranges are also possible (e.g., at least about 10 timesand less than or equal to about 1000 times higher than a controlparticle or a corresponding particle). Other ranges are also possible.

For the purposes of the comparisons described herein, the correspondingparticles may be approximately the same size, shape, and/or density asthe particles of the invention but lack the coating that makes theparticles of the invention mobile in mucus. In some embodiments, themeasurement of the geometric mean square displacement and rate ofdiffusivity of the particles (e.g., the corresponding particles andparticles of the invention) is based on a time scale of about 1 second,about 3 seconds, or about 10 seconds. Methods for determining thegeometric mean square displacement and rate of diffusivity are known inthe art. The particles of the invention may pass through mucus or amucosal barrier with a geometric mean squared displacement that is atleast about 10 times, about 30 times, about 100 times, about 300 times,about 1000 times, about 3000 times, about 10000 times higher thancorresponding particles or negative control particles. In someembodiments, the particles of the invention pass through mucus or amucosal barrier with a geometric mean squared displacement that is lessthan about 10000 times higher, less than about 3000 times higher, lessthan about 1000 times higher, less than about 300 times higher, lessthan about 100 times higher, less than about 30 times higher, or lessthan about 10 times higher than negative control particles orcorresponding particles. Combinations of the above-referenced ranges arealso possible (e.g., at least about 10 times and less than about 1000times higher than negative control particles or correspondingparticles). Other ranges are also possible.

In some embodiments, particles of the invention diffuse through amucosal barrier at a rate approaching the rate or diffusivity at whichthe particles can diffuse through water. In some embodiments, theparticles of the invention pass through a mucosal barrier at a rate ordiffusivity that is less than about 1/100, less than about 1/300, lessthan about 1/1000, less than about 1/3000, less than about 1/10,000 ofthe diffusivity that the particles diffuse through water under similarconditions. In some embodiments, particles of the invention pass througha mucosal barrier at a rate or diffusivity that is greater than or equalto about 1/10,000, greater than or equal to about 1/3000, greater thanor equal to about 1/1000, greater than or equal to about 1/300, orgreater than or equal to about 1/100 of the diffusivity that theparticles diffuse through water under similar conditions. Combinationsof the above-referenced ranges are also possible (e.g., greater than orequal to about 1/3000 and less than 1/300 the diffusivity that theparticles diffuse through water under similar conditions). Other rangesare also possible. The measurement of diffusivity may be based on a timescale of about 1 second, or about 0.5 second, or about 2 seconds, orabout 5 seconds, or about 10 seconds.

In some embodiments, the particles of the invention diffuse throughhuman cervicovaginal mucus at a diffusivity that is less than about1/500 of the diffusivity that the particles diffuse through water. Insome embodiments, the measurement of diffusivity is based on a timescale of about 1 second, or about 0.5 second, or about 2 seconds, orabout 5 seconds, or about 10 seconds.

In certain embodiments, the present invention provides particles thattravel through mucus, such as human cervicovaginal mucus, at certainabsolute diffusivities. For example, the particles of described hereinmay travel at diffusivities of at least about 1×10⁻⁴ μm/s, 2×10⁻⁴ μm/s,5×10⁻⁴ μm/s, 1×10⁻³ μm/s, 2×10⁻³ μm/s, 5×10⁻³ μm/s, 1×10⁻² μm/s, 2×10⁻²μm/s, 4×10⁻² μm/s, 5×10⁻² m/s, 6×10⁻² μm/s, 8×10⁻² μm/s, 1×10⁻¹ μm/s,2×10⁻¹ μm/s, 5×10⁻¹ μm/s, 1 μm/s, or 2 μm/s. In some cases, theparticles may travel at diffusivities of less than or equal to about 2μm/s, less than or equal to about 1 μm/s, less than or equal to about5×10⁻¹ μm/s, less than or equal to about 2×10⁻¹ μm/s, less than or equalto about 1×10⁻¹ μm/s, less than or equal to about 8×10⁻² μm/s, less thanor equal to about 6×10⁻² μm/s, less than or equal to about 5×10⁻² μm/s,less than or equal to about 4×10⁻² μm/s, less than or equal to about2×10⁻² μm/s, less than or equal to about 1×10⁻² μm/s, less than or equalto about 5×10⁻³ m/s, less than or equal to about 2×10⁻³ m/s, less thanor equal to about 1×10⁻³ m/s, less than or equal to about 5×10⁻⁴ m/s,less than or equal to about 2×10⁻⁴ m/s, or less than or equal to about1×10⁻⁴ μm/s. Combinations of the above-referenced ranges are alsopossible (e.g., greater than or equal to about 2×10⁻⁴ m/s and less thanor equal to about 1×10⁻¹ μm/s). Other ranges are also possible. In somecases, the measurement is based on a time scale of about 1 second, orabout 0.5 second, or about 2 seconds, or about 5 seconds, or about 10seconds.

It should be appreciated that while the mobility (e.g., relativevelocity and diffusivity) of the particles of the invention may bemeasured in human cervicovaginal mucus, the mobility may be measured inother types of mucus as well.

In certain embodiments, a particle described herein comprisessurface-altering moieties at a given density. The surface-alteringmoieties may be the portions of a surface-altering agent that are, forexample, exposed to the solvent containing the particle. As an example,the hydrolyzed units/blocks of PVA may be surface-altering moieties ofthe surface-altering agent PVA. In another example, the PEG segments maybe surface-altering moieties of the surface-altering agent PEG-PPO-PEG.In some cases, the surface-altering moieties and/or surface-alteringagents are present at a density of at least about 0.001 units ormolecules per nm², at least about 0.002, at least about 0.005, at leastabout 0.01, at least about 0.02, at least about 0.05, at least about0.1, at least about 0.2, at least about 0.5, at least about 1, at leastabout 2, at least about 5, at least about 10, at least about 20, atleast about 50, at least about 100 units or molecules per nm², or moreunits or molecules per nm². In some cases, the surface-altering moietiesand/or surface-altering agents are present at a density of less than orequal to about 100 units or molecules per nm², less than or equal toabout 50, less than or equal to about 20, less than or equal to about10, less than or equal to about 5, less than or equal to about 2, lessthan or equal to about 1, less than or equal to about 0.5, less than orequal to about 0.2, less than or equal to about 0.1, less than or equalto about 0.05, less than or equal to about 0.02, or less than or equalto about 0.01 units or molecules per nm². Combinations of theabove-referenced ranges are possible (e.g., a density of at least about0.01 and less than or equal to about 1 units or molecules per nm²).Other ranges are also possible. In some embodiments, the density valuesdescribed above may be an average density as the surface altering agentis in equilibrium with other components in solution.

Those skilled in the art would be aware of methods to estimate theaverage density of surface-altering moieties (see, for example, Budijonoet al., Colloids and Surfaces A: Physicochem. Eng. Aspects 2010, 360,105-110; Joshi et al., Anal. Chim. Acta 1979, 104, 153-160). Forexample, as described herein, the average density of surface-alteringmoieties can be determined using HPLC quantitation and DLS analysis. Asuspension of particles for which surface density determination is ofinterest is first sized using DLS: a small volume is diluted to anappropriate concentration (e.g., about 100 μg/mL), and the z-averagediameter is taken as a representative measurement of particle size. Theremaining suspension is then divided into two aliquots. Using HPLC, thefirst aliquot is assayed for the total concentration of core materialand for the total concentration of the surface-altering moiety. Againusing HPLC, the second aliquot is assayed for the concentration of freeor unbound surface-altering moiety. In order to get only the free orunbound surface-altering moiety from the second aliquot, the particles,and therefore any bound surface-altering moiety, are removed byultracentrifugation. By subtracting the concentration of the unboundsurface-altering moiety from the total concentration of surface-alteringmoiety, the concentration of bound surface-altering moiety can bedetermined. Since the total concentration of core material was alsodetermined from the first aliquot, the mass ratio between the corematerial and the surface-altering moiety can be determined. Using themolecular weight of the surface-altering moiety the number ofsurface-altering moiety to mass of core material can be calculated. Toturn this number into a surface density measurement, the surface areaper mass of core material needs to be calculated. The volume of theparticle is approximated as that of a sphere with the diameter obtainedfrom DLS allowing for the calculation of the surface area per mass ofcore material. In this way the number of surface-altering moieties persurface area can be determined.

In certain embodiments, the particles of the invention comprisesurface-altering moieties and/or agents that affect the zeta-potentialof the particle. The zeta potential of the particle may be, for example,at least about −100 mV, at least about −30 mV, at least about −10 mV, atleast about −3 mV, at least about 3 mV, at least about 10 mV, at leastabout 30 mV, or at least about 100 mV. The zeta potential of theparticle may also be, for example, less than about 100 mV, less thanabout 30 mV, less than about 10 mV, less than about 3 mV, less thanabout −3 mV, less than about −10 mV, less than about −30 mV, or lessthan about −100 mV. Combinations of the above-referenced ranges arepossible (e.g., a zeta-potential of at least about −30 mV and less thanabout 30 mV). Other ranges are also possible.

The coated particles described herein may have any suitable shape and/orsize. In some embodiments, a coated particle has a shape substantiallysimilar to the shape of the core. In some cases, a coated particledescribed herein may be a nanoparticle, i.e., the particle has acharacteristic dimension of less than about 1 micrometer, where thecharacteristic dimension of the particle is the diameter of a perfectsphere having the same volume as the particle. In other embodiments,larger sizes are possible (e.g., about 1-10 microns). A plurality ofparticles, in some embodiments, may also be characterized by an averagesize (e.g., an average largest cross-sectional dimension, or an averagesmallest cross-sectional dimension for the plurality of particles). Aplurality of particles may have an average size of, for example, lessthan or equal to about 10 μm, less than or equal to about 5 m, less thanor equal to about 1 m, less than or equal to about 800 nm, less than orequal to about 700 nm, less than or equal to about 500 nm, less than orequal to 400 nm, less than or equal to 300 nm, less than or equal toabout 200 nm, less than or equal to about 100 nm, less than or equal toabout 75 nm, less than or equal to about 50 nm, less than or equal toabout 40 nm, less than or equal to about 35 nm, less than or equal toabout 30 nm, less than or equal to about 25 nm, less than or equal toabout 20 nm, less than or equal to about 15 nm, or less than or equal toabout 5 nm. In some cases, a plurality of particles may have an averagesize of, for example, at least about 5 nm, at least about 20 nm, atleast about 50 nm, at least about 100 nm, at least about 200 nm, atleast about 300 nm, at least about 400 nm, at least about 500 nm, atleast about 1 μm, at least or at least about 5 μm. Combinations of theabove-referenced ranges are also possible (e.g., an average size of atleast about 50 nm and less than or equal to about 500 nm). Other rangesare also possible. In some embodiments, the sizes of the cores formed bya process described herein have a Gaussian-type distribution.

Pharmaceutical Agents

A particle or pharmaceutical composition of the invention may compriseat least one pharmaceutical agent. In certain embodiments, thepharmaceutical agent described herein is a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, tautomer, stereoisomer, isotopicallylabeled derivative, or prodrug of another pharmaceutical agent. Incertain embodiments, the pharmaceutical agent is a co-crystal withanother substance (e.g., a solvent, protein, or another pharmaceuticalagent). The pharmaceutical agent may be present in the core and/or oneor more coatings of the particle (e.g., dispersed throughout the coreand/or coating). In some embodiments, the pharmaceutical agent may bedisposed on the surface of the particle (e.g., on the outer or innersurface of the one or more coatings or on the surface of the core). Thepharmaceutical agent may be contained within the particle and/ordisposed in a portion of the particle using commonly known techniques(e.g., coating, adsorption, covalent linkage, and encapsulation). Insome embodiments, the pharmaceutical agent is present during theformation of the core. In other embodiments, the pharmaceutical agent isnot present during the formation of the core. In certain embodiments,the pharmaceutical agent is present during the coating of the core.

In some embodiments, the pharmaceutical agent contained in a particle orpharmaceutical composition of the invention has a therapeutic and/orprophylactic effect in a mucosal tissue to be targeted. Non-limitingexamples of mucosal tissues include ophthalmic, respiratory (e.g.,including nasal, pharyngeal, tracheal, and bronchial membranes), oral(e.g., including the buccal and esophagal membranes and tonsil surface),gastrointestinal (e.g., including stomach, small intestine, largeintestine, colon, rectum), nasal, and genital (e.g., including vaginal,cervical and urethral membranes) tissues.

Any suitable number of pharmaceutical agents may be present in aparticle or pharmaceutical composition of the invention. For example, atleast 1, at least 2, at least 3, at least 4, at least 5, or morepharmaceutical agents may be present in the particle or pharmaceuticalcomposition of the invention. In certain embodiments, less than 10pharmaceutical agents are present in the particle or pharmaceuticalcomposition of the invention.

In certain embodiments, the pharmaceutical agent in the particles orpharmaceutical compositions of the invention is a compound of theinvention. The pharmaceutical agent described herein (e.g., a compoundof the invention) may be encapsulated in a polymer, a lipid, a protein,or a combination thereof.

Pharmaceutical Compositions

In another aspect, the present invention provides pharmaceuticalcompositions comprising at least one particle of the invention.Pharmaceutical compositions described herein and for use in accordancewith the articles and methods described herein may include apharmaceutically acceptable excipient or carrier. A pharmaceuticallyacceptable excipient or pharmaceutically acceptable carrier may includea non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any suitable type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose, and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose, andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil; safflower oil; sesame oil; olive oil; corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; detergents such as Tween 80; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator. As would be appreciated by one of skill in this art, theexcipients may be chosen based on the route of administration asdescribed below, the pharmaceutical agent being delivered, time courseof delivery of the agent, etc.

Pharmaceutical compositions containing the particles described hereinmay be administered to a subject via any route known in the art. Theseinclude, but are not limited to, oral, sublingual, nasal, intradermal,subcutaneous, intramuscular, rectal, vaginal, intravenous,intraarterial, intracisternally, intraperitoneal, intravitreal,periocular, topical (as by powders, creams, ointments, or drops), buccaland inhalational administration. In some embodiments, compositionsdescribed herein may be administered parenterally as injections(intravenous, intramuscular, or subcutaneous), drop infusionpreparations, or suppositories. As would be appreciated by one of skillin this art, the route of administration and the effective dosage toachieve the desired biological effect may be determined by the agentbeing administered, the target organ, the preparation beingadministered, time course of administration, disease being treated,intended use, etc.

In certain embodiments, the pharmaceutical compositions are useful forthe delivery of a pharmaceutical agent described herein (e.g., acompound of the invention) through or to mucus or a mucosal surface in asubject. The pharmaceutical compositions may be delivered to the mucosalsurface in the subject and may pass through a mucosal barrier in thesubject (e.g., mucus), and/or may show prolonged retention and/orincreased uniform distribution of the particles of the invention at themucosal surface, e.g., due to reduced mucoadhesion. In certainembodiments, the pharmaceutical compositions are useful in increasingthe bioavailability of the pharmaceutical agent in the subject. Incertain embodiments, the pharmaceutical compositions are useful inincreasing the concentration of the pharmaceutical agent in the subject.In certain embodiments, the pharmaceutical compositions are useful inincreasing the exposure of the pharmaceutical agent in the subject.Moreover, the pharmaceutical compositions may be useful in treatingand/or preventing a disease (e.g., ocular disease) in a subject.

Moreover, the pharmaceutical compositions may be administeredparenterally as injections (intravenous, intramuscular, orsubcutaneous), drop infusion preparations, or suppositories. Forophthalmic applications, the pharmaceutical compositions may beadministered by injection (e.g., intraocular, intrastromal,intravitreal, or intracameral), or by the ophthalmic mucous membraneroute, the pharmaceutical compositions may be administered topically,such as suspensions (e.g., eye drops) or ointments.

In some embodiments, particles described herein that may be administeredin inhalant or aerosol formulations comprise one or more pharmaceuticalagents, such as adjuvants, diagnostic agents, imaging agents, ortherapeutic agents useful in inhalation therapy. The particle size ofthe particulate medicament should be such as to permit inhalation ofsubstantially all of the medicament into the lungs upon administrationof the aerosol formulation and may be, for example, less than about 20microns, e.g., in the range of about 1 to about 10 microns, e.g., about1 to about 5 microns, although other ranges are also possible. Theparticle size of the medicament may be reduced by conventional means,for example by milling or micronization. Alternatively, the particulatemedicament can be administered to the lungs via nebulization of asuspension. The final aerosol formulation may contain, for example,between 0.005-90% w/w, between 0.005-50%, between 0.005-10%, betweenabout 0.005-5% w/w, or between 0.01-1.0% w/w, of medicament relative tothe total weight of the formulation. Other ranges are also possible.

It is desirable, but by no means required, that the formulationsdescribed herein contain no components which may provoke the degradationof stratospheric ozone. In particular, in some embodiments, propellantsare selected that do not contain or do not consist essentially ofchlorofluorocarbons such as CCl₃F, CCl₂F₂, and CF₃CCl₃.

The aerosol may comprise propellant. The propellant may optionallycontain an adjuvant having a higher polarity and/or a higher boilingpoint than the propellant. Polar adjuvants which may be used include(e.g., C₂₋₆) aliphatic alcohols and polyols such as ethanol,isopropanol, and propylene glycol, preferably ethanol. In general, onlysmall quantities of polar adjuvants (e.g., 0.05-3.0% w/w) may berequired to improve the stability of the dispersion—the use ofquantities in excess of 5% w/w may tend to dissolve the medicament.Formulations in accordance with the embodiments described herein maycontain less than 1% w/w, e.g., about 0.1% w/w, of polar adjuvant.However, the formulations described herein may be substantially free ofpolar adjuvants, especially ethanol. Suitable volatile adjuvants includesaturated hydrocarbons such as propane, n-butane, isobutane, pentane andisopentane and alkyl ethers such as dimethyl ether. In general, up to50% w/w of the propellant may comprise a volatile adjuvant, for example,up to 30% w/w of a volatile saturated C₁-C₆ hydrocarbon. Optionally, theaerosol formulations according to the invention may further comprise oneor more surfactants. The surfactants can be physiologically acceptableupon administration by inhalation. Within this category are includedsurfactants such as L-α-phosphatidylcholine (PC),1,2-dipalmitoylphosphatidycholine (DPPC), oleic acid, sorbitantrioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylenesorbitan monolaurate, polyoxyethylene sorbitan monooleate, naturallecithin, oleyl polyoxyethylene ether, stearyl polyoxyethylene ether,lauryl polyoxyethylene ether, block copolymers of oxyethylene andoxypropylene, synthetic lecithin, diethylene glycol dioleate,tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glycerylmonooleate, glyceryl monostearate, glyceryl monoricinoleate, cetylalcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridiniumchloride, benzalkonium chloride, olive oil, glyceryl monolaurate, cornoil, cotton seed oil, and sunflower seed oil.

The formulations described herein may be prepared by dispersal of theparticles in the selected propellant and/or co-propellant in anappropriate container, e.g., with the aid of sonication. The particlesmay be suspended in co-propellant and filled into a suitable container.The valve of the container is then sealed into place and the propellantintroduced by pressure filling through the valve in the conventionalmanner. The particles may be thus suspended or dissolved in a liquifiedpropellant, sealed in a container with a metering valve and fitted intoan actuator. Such metered dose inhalers are well known in the art. Themetering valve may meter 10 to 500 L and preferably 25 to 150 μL. Incertain embodiments, dispersal may be achieved using dry powder inhalers(e.g., spinhaler) for the particles (which remain as dry powders). Inother embodiments, nanospheres, may be suspended in an aqueous fluid andnebulized into fine droplets to be aerosolized into the lungs.

Sonic nebulizers may be used because they minimize exposing the agent toshear, which may result in degradation of the particles. Ordinarily, anaqueous aerosol is made by formulating an aqueous solution or suspensionof the particles together with conventional pharmaceutically acceptablecarriers and stabilizers. The carriers and stabilizers vary with therequirements of the particular composition, but typically includenon-ionic surfactants (Tweens, Pluronic®, or polyethylene glycol),innocuous proteins like serum albumin, sorbitan esters, oleic acid,lecithin, amino acids such as glycine, buffers, salts, sugars, or sugaralcohols. Aerosols generally are prepared from isotonic solutions.

The compositions and/or formulations described herein may have anysuitable osmolarity. In some embodiments, a composition and/orformulation described herein may have an osmolarity of at least about 0mOsm/L, at least about 5 mOsm/L, at least about 25 mOsm/L, at leastabout 50 mOsm/L, at least about 75 mOsm/L, at least about 100 mOsm/L, atleast about 150 mOsm/L, at least about 200 mOsm/L, at least about 250mOsm/L, or at least about 310 mOsm/L. In certain embodiments, acomposition and/or formulation described herein may have an osmolarityof less than or equal to about 310 mOsm/L, less than or equal to about250 mOsm/L, less than or equal to about 200 mOsm/L, less than or equalto about 150 mOsm/L, less than or equal to about 100 mOsm/L, less thanor equal to about 75 mOsm/L, less than or equal to about 50 mOsm/L, lessthan or equal to about 25 mOsm/L, or less than or equal to about 5mOsm/L. Combinations of the above-referenced ranges are also possible(e.g., an osmolarity of at least about 0 mOsm/L and less than or equalto about 50 mOsm/L). Other ranges are also possible. The osmolarity ofthe composition and/or formulation can be varied by changing, forexample, the concentration of salts present in the solvent of thecomposition and/or formulation.

The pharmaceutical composition of the invention may include one or morepharmaceutical agents described herein, such as a compound of theinvention. In certain embodiments, the pharmaceutical compositionincludes a plurality of particles of the invention that comprise one ormore pharmaceutical agents in the core and/or coating of the particles.In some embodiments, the ratio of surface-altering agent topharmaceutical agent (or salt thereof) may be at least 0.001:1 (weightratio, molar ratio, or w:v ratio), at least 0.01:1, at least 0.01:1, atleast 1:1, at least 2:1, at least 3:1, at least 5:1, at least 10:1, atleast 25:1, at least 50:1, at least 100:1, or at least 500:1. In somecases, the ratio of surface-altering agent to pharmaceutical agent (orsalt thereof) may be less than or equal to 1000:1 (weight ratio or molarratio), less than or equal to 500:1, less than or equal to 100:1, lessthan or equal to 75:1, less than or equal to 50:1, less than or equal to25:1, less than or equal to 10:1, less than or equal to 5:1, less thanor equal to 3:1, less than or equal to 2:1, less than or equal to 1:1,or less than or equal to 0.1:1. Combinations of the above-referencedranges are possible (e.g., a ratio of at least 5:1 and less than orequal to 50:1). Other ranges are also possible. In some embodiments, thepharmaceutical composition of the invention includes the above-notedranges for the ratio of the weight of each one of the pharmaceuticalagents to the weight of each one of the one or more surface-alteringagents during a formation process and/or a dilution process describedherein. In certain embodiments, the pharmaceutical composition includesthe above-noted ranges for the ratio of the weight of each one of thepharmaceutical agents to the weight of each one of the one or moresurface-altering agents immediately prior to the pharmaceuticalcomposition being administered to a subject or contacted with abiological sample. The pharmaceutical agent may be present in thepharmaceutical composition of the invention in any suitable amount,e.g., at least about 0.01 wt %, at least about 0.1 wt %, at least about1 wt %, at least about 5 wt %, at least about 10 wt %, at least about 30wt % of the pharmaceutical composition. In some cases, thepharmaceutical agent may be present in the pharmaceutical composition atless than about 30 wt %, less than about 10 wt %, less than about 5 wt%, less than about 2 wt %, or less than about 1 wt % of thepharmaceutical composition. Combinations of the above-referenced rangesare also possible (e.g., present in an amount of at least about 0.1 wt %and less than about 10 wt % of the pharmaceutical composition). Otherranges are also possible. In certain embodiments, the pharmaceuticalagent is about 0.1-2 wt % of the pharmaceutical composition. In certainembodiments, the pharmaceutical agent is about 2-20 wt % of thepharmaceutical composition. In certain embodiments, the pharmaceuticalagent is about 0.2 wt %, about 0.4 wt %, about 1 wt %, about 2 wt %,about 5 wt %, or about 10 wt % of the pharmaceutical composition.

In one set of embodiments, a composition and/or formulation includes oneor more chelating agents. A chelating agent used herein refers to achemical compound that has the ability to react with a metal ion to forma complex through one or more bonds. The one or more bonds are typicallyionic or coordination bonds. The chelating agent can be an inorganic oran organic compound. A metal ion capable of catalyzing certain chemicalreactions (e.g., oxidation reactions) may lose its catalytic activitywhen the metal ion is bound to a chelating agent to form a complex.Therefore, a chelating agent may show preservative properties when itbinds to a metal ion. Any suitable chelating agent that has preservativeproperties can be used, such as phosphonic acids, aminocarboxylic acids,hydroxycarboxylic acids, polyamines, aminoalcohols, and polymericchelating agents. Specific examples of chelating agents include, but arenot limited to, ethylenediaminetetraacetic acid (EDTA), nitrilotriaceticacid (NTA), diethylenetriaminepentacetic acid (DTPA),N-hydroxyethylethylene diaminetriacetic acid (HEDTA), tetraborates,triethylamine diamine, and salts and derivatives thereof. In certainembodiments, the chelating agent is EDTA. In certain embodiments, thechelating agent is a salt of EDTA. In certain embodiments, the chelatingagent is disodium EDTA.

In certain embodiments, the pharmaceutical composition includes aplurality of particles of the invention that comprise the chelatingagent in the formulation containing the particles. In certainembodiments, the concentration of the chelating agent is greater than orequal to about 0 wt %, greater than or equal to about 0.0001 wt %,greater than or equal to about 0.003 wt %, greater than or equal toabout 0.01 wt %, greater than or equal to about 0.03 wt %, greater thanor equal to about 0.05 wt %, greater than or equal to about 0.1 wt %,greater than or equal to about 0.3 wt %, greater than or equal to about1 wt %, or greater than or equal to about 3 wt %. In certainembodiments, the concentration of the chelating agent is less than orequal to about 3 wt %, less than or equal to about 1 wt %, less than orequal to about 0.3 wt %, less than or equal to about 0.1 wt %, less thanor equal to about 0.05 wt %, less than or equal to about 0.03 wt %, lessthan or equal to about 0.01 wt %, less than or equal to about 0.003 wt%, less than or equal to about 0.001 wt %, or less than or equal toabout 0.0003 wt %. Combinations of the above-noted ranges are possible(e.g., a concentration of greater than or equal to about 0.01 wt % andless than or equal to about 0.3 wt %). Other ranges are also possible.In certain embodiments, the concentration of the chelating agent isabout 0.001-0.1 wt %. In certain embodiments, the concentration of thechelating agent is about 0.005 wt %. In certain embodiments, theconcentration of the chelating agent is about 0.01 wt %. In certainembodiments, the concentration of the chelating agent is about 0.05 wt%. In certain embodiments, the concentration of the chelating agent isabout 0.1 wt %.

In some embodiments, an antimicrobial agent may be included in acomposition and/or formulation including the coated particles describedherein. An antimicrobial agent used herein refers to a bioactive agenteffective in the inhibition of, prevention of, or protection againstmicroorganisms such as bacteria, microbes, fungi, viruses, spores,yeasts, molds, and others generally associated with infections. Examplesof antimicrobial agents include cephaloporins, clindamycin,chlorampheanicol, carbapenems, minocyclines, rifampin, penicillins,monobactams, quinolones, tetracycline, macrolides, sulfa antibiotics,trimethoprim, fusidic acid, aminoglycosides, amphotericin B, azoles,flucytosine, cilofungin, bactericidal nitrofuran compounds,nanoparticles of metallic silver or an alloy of silver containing about2.5 wt % copper, silver citrate, silver acetate, silver benzoate,bismuth pyrithione, zinc pyrithione, zinc percarbonates, zincperborates, bismuth salts, parabens (e.g., methyl-, ethyl-, propyl-,butyl-, and octyl-benzoic acid esters), citric acid, benzalkoniumchloride (BAC), rifamycin, and sodium percarbonate.

In certain embodiments, the pharmaceutical composition includes aplurality of particles of the invention that comprise the antimicrobialagent in the formulation containing the particles. In certainembodiments, the concentration of the antimicrobial agent may be greaterthan or equal to about 0 wt %, greater than or equal to about 0.0001 wt%, greater than or equal to about 0.003 wt %, greater than or equal toabout 0.01 wt %, greater than or equal to about 0.03 wt %, greater thanor equal to about 0.1 wt %, greater than or equal to about 0.3 wt %,greater than or equal to about 1 wt %, or greater than or equal to about3 wt %. In certain embodiments, the concentration of the antimicrobialagent may be less than or equal to about 3 wt %, less than or equal toabout 1 wt %, less than or equal to about 0.3 wt %, less than or equalto about 0.1 wt %, less than or equal to about 0.03 wt %, less than orequal to about 0.01 wt %, less than or equal to about 0.003 wt %, lessthan or equal to about 0.001 wt %, or less than or equal to about 0.0003wt %. Combinations of the above-noted ranges are possible (e.g., aconcentration of greater than or equal to about 0.001 wt % and less thanor equal to about 0.1 wt %). Other ranges are also possible. In certainembodiments, the concentration of the antimicrobial agent is about0.001-0.05 wt %. In certain embodiments, the concentration of theantimicrobial agent is about 0.002 wt %. In certain embodiments, theconcentration of the antimicrobial agent is about 0.005 wt %. In certainembodiments, the concentration of the antimicrobial agent is about 0.01wt %. In certain embodiments, the concentration of the antimicrobialagent is about 0.02 wt %. In certain embodiments, the concentration ofthe antimicrobial agent is about 0.05 wt %.

In some embodiments, a tonicity agent may be included in a compositionand/or formulation including the coated particles described herein. Atonicity agent used herein refers to a compound or substance that can beused to adjust the composition of a formulation to the desiredosmolarity range. In certain embodiments, the desired osmolarity rangeis an isotonic range compatible with blood. In certain embodiments, thedesired osmolarity range is hypotonic. In certain embodiments, thedesired osmolarity range is hypertonic. Examples of tonicity agentsinclude glycerin, lactose, mannitol, dextrose, sodium chloride, sodiumsulfate, sorbitol, saline-sodium citrate (SSC), and the like. In certainembodiments, a combination of one or more tonicity agents may be used.In certain embodiments, the tonicity agent is glycerin. In certainembodiments, the tonicity agent is sodium chloride.

A tonicity agent (such as one described herein) may be present at asuitable concentration in a composition and/or formulation including thecoated particles described herein. In certain embodiments, theconcentration of the tonicity agent is greater than or equal to about 0wt %, greater than or equal to about 0.001 wt %, greater than or equalto about 0.03 wt %, greater than or equal to about 0.1 wt %, greaterthan or equal to about 0.3 wt %, greater than or equal to about 1 wt %,greater than or equal to about 3 wt %, greater than or equal to about 10wt %, greater than or equal to about 20 wt %, or greater than or equalto about 30 wt %. In certain embodiments, the concentration of thetonicity agent is less than or equal to about 30 wt %, less than orequal to about 10 wt %, less than or equal to about 3 wt %, less than orequal to about 1 wt %, less than or equal to about 0.3 wt %, less thanor equal to about 0.1 wt %, less than or equal to about 0.03 wt %, lessthan or equal to about 0.01 wt %, or less than or equal to about 0.003wt %. Combinations of the above-noted ranges are possible (e.g., aconcentration of greater than or equal to about 0.1 wt % and less thanor equal to about 10 wt %). Other ranges are also possible. In certainembodiments, the concentration of the tonicity agent is about 0.1-1%. Incertain embodiments, the concentration of the tonicity agent is about0.5-3%. In certain embodiments, the concentration of the tonicity agentis about 0.25 wt %. In certain embodiments, the concentration of thetonicity agent is about 0.45 wt %. In certain embodiments, theconcentration of the tonicity agent is about 0.9 wt %. In certainembodiments, the concentration of the tonicity agent is about 1.2 wt %.In certain embodiments, the concentration of the tonicity agent is about2.4 wt %. In certain embodiments, the concentration of the tonicityagent is about 5 wt %.

In some embodiments, a composition and/or formulation described hereinmay have an osmolarity of at least about 0 mOsm/L, at least about 5mOsm/L, at least about 25 mOsm/L, at least about 50 mOsm/L, at leastabout 75 mOsm/L, at least about 100 mOsm/L, at least about 150 mOsm/L,at least about 200 mOsm/L, at least about 250 mOsm/L, at least about 310mOsm/L, or at least about 450 mOsm/L. In certain embodiments, acomposition and/or formulation described herein may have an osmolarityof less than or equal to about 450 mOsm/L, less than or equal to about310 mOsm/L, less than or equal to about 250 mOsm/L, less than or equalto about 200 mOsm/L, less than or equal to about 150 mOsm/L, less thanor equal to about 100 mOsm/L, less than or equal to about 75 mOsm/L,less than or equal to about 50 mOsm/L, less than or equal to about 25mOsm/L, or less than or equal to about 5 mOsm/L. Combinations of theabove-referenced ranges are also possible (e.g., an osmolarity of atleast about 0 mOsm/L and less than or equal to about 50 mOsm/L). Otherranges are also possible.

It is appreciated in the art that the ionic strength of an inventivepharmaceutical composition that comprises a plurality of particles ofthe invention may affect the polydispersity of the plurality of theparticles. The ionic strength may also affect the colloidal stability ofthe plurality of the particles. For example, a relatively high ionicstrength of the pharmaceutical composition may cause the plurality ofparticles to coagulate and therefore may destabilize the pharmaceuticalcomposition. In some embodiments, the pharmaceutical composition isstabilized by repulsive inter-particle forces. For example, theplurality of particles may be electrically or electrostatically charged.Two charged particles may repel each other, preventing collision andaggregation. When the repulsive inter-particle forces weaken or becomeattractive, the plurality of particles may start to aggregate. Forinstance, when the ionic strength of the pharmaceutical composition isincreased to a certain level, the charges (e.g., negative charges) ofthe plurality of particles may be neutralized by the oppositely chargedions present in the pharmaceutical composition (e.g., Na⁺ ions insolution). As a result, the plurality of particles may collide and bondto each other to form aggregates (e.g., clusters or flocs) of largersizes. The formed aggregates of particles may also differ in size, andthus the polydispersity of the pharmaceutical composition may alsoincrease. For example, an inventive pharmaceutical compositioncomprising similarly-sized particles may become a pharmaceuticalcomposition comprising particles having various sizes (e.g., due toaggregation) when the ionic strength of the pharmaceutical compositionis increased beyond a certain level. In the course of aggregation, theaggregates may grow in size and eventually settle to the bottom of thecontainer, and the pharmaceutical composition is considered colloidallyunstable. Once the plurality of particles in a pharmaceuticalcomposition form aggregates, it is usually difficult to disrupt theaggregates into individual particles.

Certain pharmaceutical compositions of the invention show unexpectedproperties in that, among other things, the presence of one or moreionic tonicity agents (e.g., a salt, such as NaCl) in the pharmaceuticalcompositions at certain concentrations actually decreases or maintainsthe degree of aggregation of the particles present in the pharmaceuticalcompositions, and/or does not significantly increase aggregation. Incertain embodiments, the polydispersity of the pharmaceuticalcomposition decreases, is relatively constant, or does not change by anappreciable amount upon addition of one or more ionic tonicity agentsinto the pharmaceutical composition. For example, in some embodiments,the polydispersity of a pharmaceutical composition is relativelyconstant in the presence of added ionic strength and/or when the addedionic strength of the pharmaceutical composition is kept relativelyconstant or increased (e.g., during a formation and/or dilution processdescribed herein). In certain embodiments, when the ionic strengthincreases by at least 50%, the polydispersity increases by less thanabout 300%, less than about 100%, less than about 30%, less than about10%, less than about 3%, or less than about 1%. In certain embodiments,when the ionic strength is increased by at least 50%, the polydispersityincreases by greater than or equal to about 1%, greater than or equal toabout 3%, greater than or equal to about 10%, greater than or equal toabout 30%, or greater than or equal to about 100%. Combinations of theabove-noted ranges are possible (e.g., an increase in polydispersity ofless than 30% and greater than or equal to 3%). Other ranges are alsopossible.

The ionic strength of a pharmaceutical composition of the invention maybe controlled (e.g., increased, decreased, or maintained) through avariety of means, such as the addition of one or more ionic tonicityagents (e.g., a salt, such as NaCl) to the pharmaceutical composition.In certain embodiments, the ionic strength of a pharmaceuticalcomposition of the invention is greater than or equal to about 0 M,greater than or equal to about 0.0003 M, greater than or equal to about0.001 M, greater than or equal to about 0.003 M, greater than or equalto about 0.01 M, greater than or equal to about 0.03 M, greater than orequal to about 0.1 M, greater than or equal to about 0.3 M, greater thanor equal to about 1 M, greater than or equal to about 3 M, or greaterthan or equal to about 10 M. In certain embodiments, the ionic strengthof a pharmaceutical composition of the invention is less than about 10M, less than about 3 M, less than about 1 M, less than about 0.3 M, lessthan about 0.1 M, less than about 0.03 M, less than about 0.01 M, lessthan about 0.003 M, less than about 0.001 M, or less than about 0.0003M. Combinations of the above-noted ranges are possible (e.g., an ionicstrength of greater than or equal to about 0.01 M and less than about 1M). Other ranges are also possible. In certain embodiments, the ionicstrength of a pharmaceutical composition of the invention is about 0.1M, about 0.15 M, or about 0.3 M.

In certain embodiments, the polydispersity of a pharmaceuticalcomposition does not change upon addition of one or more ionic tonicityagents into the pharmaceutical composition. In certain embodiments, thepolydispersity does not significantly increase upon addition of one ormore ionic tonicity agents into the pharmaceutical composition. Incertain embodiments, the polydispersity increases to a level describedherein upon addition of one or more ionic tonicity agents into thepharmaceutical composition.

The polydispersity of an inventive pharmaceutical composition thatcomprises a plurality of particles of the invention may be measured bythe polydispersity index (PDI). In certain embodiments, the PDI of thepharmaceutical composition is less than about 1, less than about 0.8,less than about 0.6, less than about 0.4, less than about 0.3, less thanabout 0.2, less than about 0.15, less than about 0.1, less than about0.05, less than about 0.01, or less than about 0.005. In certainembodiments, the PDI of the pharmaceutical composition is greater thanor equal to about 0.005, greater than or equal to about 0.01, greaterthan or equal to about 0.05, greater than or equal to about 0.1, greaterthan or equal to about 0.15, greater than or equal to about 0.2, greaterthan or equal to about 0.3, greater than or equal to about 0.4, greaterthan or equal to about 0.6, greater than or equal to about 0.8, orgreater than or equal to about 1. Combinations of the above-noted rangesare possible (e.g., a PDI of greater than or equal to about 0.1 and lessthan about 0.5). Other ranges are also possible. In certain embodiments,the PDI of the pharmaceutical composition is about 0.1, about 0.15, orabout 0.2. In certain embodiments, the pharmaceutical composition ishighly dispersible and does not tend to form aggregates. Even when theparticles do form aggregates, the aggregates may be easily broken upinto individual particles without rigorously agitating thepharmaceutical composition.

For example, in some embodiments, the polydispersity of a compositionand/or formulation is relatively constant in the presence of added ionicstrength and/or when the added ionic strength of the composition and/orformulation is kept relatively constant or increased (e.g., during aformation and/or dilution process). In certain embodiments, when theionic strength increases by at least 50%, the polydispersity increasesby less than or equal to about 200%, less than or equal to about 150%,less than or equal to about 100%, less than or equal to about 75%, lessthan or equal to about 50%, less than or equal to about 30%, less thanor equal to about 20%, less than or equal to about 10%, less than orequal to about 3%, or less than or equal to about 1%. In certainembodiments, when the ionic strength is increased by at least 50%, thepolydispersity increases by greater than or equal to about 1%, greaterthan or equal to about 3%, greater than or equal to about 10%, greaterthan or equal to about 30%, or greater than or equal to about 100%.Combinations of the above-noted ranges are possible (e.g., an increasein polydispersity of less than or equal to 50% and greater than or equalto 1%). Other ranges are also possible.

The ionic strength of a formulation described herein may be controlled(e.g., increased) through a variety of means, such as the addition ofone or more ionic tonicity agents (e.g., a salt such as NaCl) to theformulation. In certain embodiments, the ionic strength of a formulationdescribed herein is greater than or equal to about 0.0005 M, greaterthan or equal to about 0.001 M, greater than or equal to about 0.003 M,greater than or equal to about 0.01 M, greater than or equal to about0.03 M, greater than or equal to about 0.1 M, greater than or equal toabout 0.3 M, greater than or equal to about 1 M, greater than or equalto about 3 M, or greater than or equal to about 10 M. In certainembodiments, the ionic strength of a formulation described herein isless than or equal to about 10 M, less than or equal to about 3 M, lessthan or equal to about 1 M, less than or equal to about 0.3 M, less thanor equal to about 0.1 M, less than or equal to about 0.03 M, less thanor equal to about 0.01 M, less than or equal to about 0.003 M, less thanor equal to about 0.001 M, or less than or equal to about 0.0005 M.Combinations of the above-noted ranges are possible (e.g., an ionicstrength of greater than or equal to about 0.01 M and less than or equalto about 1 M). Other ranges are also possible. In certain embodiments,the ionic strength of a formulation described herein is about 0.1 M. Incertain embodiments, the ionic strength of a formulation describedherein is about 0.15 M. In certain embodiments, the ionic strength of aformulation described herein is about 0.3 M.

Generally, it is desired that a formulation is sterile before or uponadministration to a subject. A sterile formulation is essentially freeof pathogenic microorganisms, such as bacteria, microbes, fungi,viruses, spores, yeasts, molds, and others generally associated withinfections. In some embodiments, compositions and/or formulationsincluding the coated particles described herein may be subject to anaseptic process and/or other sterilization process. An aseptic processtypically involves sterilizing the components of a formulation, finalformulation, and/or container closure of a drug product through aprocess such as heat, gamma irradiation, ethylene oxide, or filtrationand then combining in a sterile environment. In some cases, an asepticprocess is preferred. In other embodiments, terminal sterilization ispreferred.

Examples of other sterilization methods include radiation sterilization(e.g., gamma, electron, or x-ray radiation), heat sterilization, sterilefiltration, and ethylene oxide sterilization. The terms “radiation” and“irradiation” are used herein interchangeably. Unlike othersterilization methods, radiation sterilization has the advantage of highpenetrating ability and instantaneous effects, without the need tocontrol temperature, pressure, vacuum, or humidity in some instances. Incertain embodiments, the radiation used to sterilize the coatedparticles described herein is gamma radiation. Gamma radiation may beapplied in an amount sufficient to kill most or substantially all of themicrobes in or on the coated particles. The temperature of the coatedparticles described herein and the rate of radiation may be relativelyconstant during the entire gamma radiation period. Gamma irradiation maybe performed at any suitable temperature (e.g., ambient temperature,about 40° C., between about 30 to about 50° C.). Unless otherwiseindicated, measurements of gamma irradiation described herein refer toones performed at about 40° C.

In embodiments in which a sterilization process is used, it may bedesired that the process does not: (1) significantly change the particlesize of the coated particles described herein; (2) significantly changethe integrity of the active ingredient (such as a drug) of the coatedparticles described herein; and (3) generate unacceptable concentrationsof impurities during or following the process. In certain embodiments,the impurities generated during or following the process are degradantsof the active ingredient of the coated particles described herein.

In certain embodiments, a process used to sterilize a composition and/orformulation described herein results in the presence of one or moredegradants in the formulation at less than or equal to about 10 wt %(relative to the weight of the undegraded drug), less than or equal toabout 3 wt %, less than or equal to about 2 wt %, less than or equal toabout 1.5 wt %, less than or equal to about 1 wt %, less than or equalto about 0.9 wt %, less than or equal to about 0.8 wt %, less than orequal to about 0.7 wt %, less than or equal to about 0.6 wt %, less thanor equal to about 0.5 wt %, less than or equal to about 0.4 wt %, lessthan or equal to about 0.3 wt %, less than or equal to about 0.2 wt %,less than or equal to about 0.15 wt %, less than or equal to about 0.1wt %, less than or equal to about 0.03 wt %, less than or equal to about0.01 wt %, less than or equal to about 0.003 wt %, or less than or equalto about 0.001 wt %. In some embodiments, the process results in adegradant in the formulation at greater than or equal to about 0.001 wt%, greater than or equal to about 0.003 wt %, greater than or equal toabout 0.01 wt %, greater than or equal to about 0.03 wt %, greater thanor equal to about 0.1 wt %, greater than or equal to about 0.3 wt %,greater than or equal to about 1 wt %, greater than or equal to about 3wt %, or greater than or equal to about 10 wt %. Combinations of theabove-referenced ranges are also possible (e.g., less than or equal toabout 1 wt % and greater than or equal to about 0.01 wt %). Other rangesare also possible.

When gamma irradiation is used in a sterilization process, thecumulative amount of the gamma radiation used may vary. In certainembodiments, the cumulative amount of the gamma radiation is greaterthan or equal to about 0.1 kGy, greater than or equal to about 0.3 kGy,greater than or equal to about 1 kGy, greater than or equal to about 3kGy, greater than or equal to about 10 kGy, greater than or equal toabout 30 kGy, greater than or equal to about 100 kGy, or greater than orequal to about 300 kGy. In certain embodiments, the cumulative amount ofthe gamma radiation is less than or equal to about 0.1 kGy, less than orequal to about 0.3 kGy, less than or equal to about 1 kGy, less than orequal to about 3 kGy, less than or equal to about 10 kGy, less than orequal to about 30 kGy, less than or equal to about 100 kGy, or less thanor equal to about 300 kGy. Combinations of the above-noted ranges arepossible (e.g., greater than or equal to about 1 kGy and less than orequal to about 30 kGy). Other ranges are also possible. In certainembodiments, multiple doses of radiation are utilized to achieve adesired cumulative radiation dosage.

The compositions and/or formulations described herein may have anysuitable pH values. The term “pH,” unless otherwise provided, refers topH measured at ambient temperature (e.g., about 20° C., about 23° C., orabout 25° C.). The compositions and/or formulations have, for example,an acidic pH, a neutral pH, or a basic pH and may depend on, forexample, where the compositions and/or formulations are to be deliveredin the body. In certain embodiments, the compositions and/orformulations have a physiological pH. In certain embodiments, the pHvalue of the compositions and/or formulations is at least about 1, atleast about 2, at least about 3, at least about 4, at least about 5, atleast about 6, at least about 6.2, at least about 6.4, at least about6.6, at least about 6.8, at least about 7, at least about 7.2, at leastabout 7.4, at least about 7.6, at least about 7.8, at least about 8, atleast about 8.2, at least about 8.4, at least about 8.6, at least about8.8, at least about 9, at least about 10, at least about 11, or at leastabout 12. In certain embodiments, the pH value of the compositionsand/or formulations is less than or equal to about 12, less than orequal to about 11, less than or equal to about 10, less than or equal toabout 9, less than or equal to about 8.8, less than or equal to about8.6, less than or equal to about 8.4, less than or equal to about 8.2,less than or equal to about 8, less than or equal to about 7.8, lessthan or equal to about 7.6, less than or equal to about 7.4, less thanor equal to about 7.2, less than or equal to about 7, less than or equalto about 6.8, less than or equal to about 6.6, less than or equal toabout 6.4, less than or equal to about 6.2, less than or equal to about6, less than or equal to about 5, less than or equal to about 4, lessthan or equal to about 3, less than or equal to about 2, or less than orequal to about 1. Combinations of the above-noted ranges are possible(e.g., a pH value of at least about 5 and less than or equal to about8.2). Other ranges are also possible. In certain embodiments, the pHvalue of the compositions and/or formulations described herein is atleast about 5 and less than or equal to about 8.

In some embodiments, the particles, compositions, and/or formulationsdescribed herein increase the ocular bioavailability of a pharmaceuticalagent by at least about 10%, at least about 20%, at least about 30%, atleast about 40%, at least about 50%, at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 100%, atleast about 150%, at least about 200%, at least about 5 fold, at leastabout 10 fold, at least about 20 fold, at least about 50 fold, at leastabout 100 fold, at least about 500 fold, or at least about 1000 fold. Incertain embodiments the particles, compositions, and/or formulationsdescribed herein increase the ocular bioavailability of a pharmaceuticalagent by less than or equal to about 1000 fold, less than or equal toabout 500 fold, less than or equal to about 100 fold, less than or equalto about 50 fold, less than or equal to about 20 fold, less than orequal to about 10 fold, less than or equal to about 5 fold, less than orequal to about 200%, less than or equal to about 150%, less than orequal to about 100%, less than or equal to about 90%, less than or equalto about 80%, less than or equal to about 70%, less than or equal toabout 60%, less than or equal to about 50%, less than or equal to about40%, less than or equal to about 30%, less than or equal to about 20%,or less than or equal to about 10%. Combinations of the above-referencedranges are also possible (e.g., an increase of at least about 10% andless than or equal to about 10 fold). Other ranges are also possible. Insome instances, the AUC of a pharmaceutical agent increases at a tissueand/or fluid in the front of the eye. In other instances, the AUC of apharmaceutical agent increases at a tissue and/or fluid in the back ofthe eye.

In general, an increase in ocular bioavailability may be calculated bytaking the difference in the AUC measured in an ocular tissue ofinterest (e.g., in aqueous humor) between those of a test compositionand a control composition, and dividing the difference by thebioavailability of the control composition. A test composition mayinclude particles comprising a pharmaceutical agent, and the particlesmay be characterized as being mucus penetrating (e.g., having a relativevelocity in mucus of greater than about 0.5, or another other relativevelocity described herein). A control composition may include particlescomprising the same pharmaceutical agent as that present in the testcomposition, the particles having a substantially similar size as thoseof the test composition, but which are not mucus penetrating (e.g.,having a relative velocity in mucus of less than or equal to about 0.5,or another other relative velocity described herein).

Ocular bioavailability of a pharmaceutical agent may be measured in anappropriate animal model (e.g. in a New Zealand white rabbit model). Theconcentration of a pharmaceutical agent and, when appropriate, itsmetabolite(s), in appropriate ocular tissues or fluids is measured as afunction of time after administration.

Other methods of measuring ocular bioavailability of a pharmaceuticalagent are possible.

In some embodiments, the concentration of a pharmaceutical agent in anocular tissue and/or fluid may be increased when the pharmaceuticalagent is delivered (e.g., via topical administration to the eye) usingthe particles, compositions, and/or formulations described hereincompared to when the pharmaceutical agent is delivered using certainexisting particles, compositions, and/or formulations that contain thesame the pharmaceutical agent (or compared to the delivery of the samepharmaceutical agent (e.g., of similar size) as the coated particle inquestion, but which does not include the coating). In certainembodiments, a dose of the particles, compositions, and/or formulationsis administered, followed by the measurement of the concentration of thepharmaceutical agent in a tissue and/or fluid of the eye. For purposesof comparison, the amount of the pharmaceutical agent included in theadministered dose of the particles, compositions, and/or formulationsdescribed herein may be similar or substantially equal to the amount ofthe pharmaceutical agent included in the administered dose of theexisting particles, compositions, and/or formulations. In certainembodiments, the concentration of the pharmaceutical agent in a tissueand/or fluid of the eye is measured at a certain time subsequent to theadministration (“time post-dose”) of a dose of the particles,compositions, and/or formulations described herein or of the existingparticles, compositions, and/or formulations. In certain embodiments,the time when the concentration is measured is about 1 min, about 10min, about 30 min, about 1 h, about 2 h, about 3 h, about 4 h, about 5h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h,about 12 h, about 18 h, about 24 h, about 36 h, or about 48 h,post-dose.

In some embodiments, the concentration of the pharmaceutical agent in atissue and/or fluid may increase due to, at least in part, a coating oncore particles comprising the pharmaceutical agent that renders theparticles mucus penetrating, compared to particles of the samepharmaceutical agent (e.g., of similar size) as the coated particle inquestion, but which does not include the coating. In some embodiments,the particles, compositions, and/or formulations described hereinincreases the concentration of a pharmaceutical agent in a tissue and/orfluid by at least about 10%, at least about 20%, at least about 30%, atleast about 40%, at least about 50%, at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 100%, atleast about 200%, at least about 300%, at least about 400%, at leastabout 500%, or at least about 10 fold, at least about 20 fold, at leastabout 50 fold, at least about 100 fold, at least about 1000 fold, atleast about 10⁴ fold, at least about 10⁵ fold, or at least about 10⁶fold. In some cases, the particles, compositions, and/or formulationsdescribed herein increases the concentration of a pharmaceutical agentin a tissue and/or fluid by less than or equal to about 10⁶ fold, lessthan or equal to about 10⁵ fold, less than or equal to about 10⁴ fold,1000 fold, less than or equal to about 100 fold, less than or equal toabout 10 fold, less than or equal to about 500%, less than or equal toabout 400%, less than or equal to about 300%, less than or equal toabout 200%, less than or equal to about 100%, less than or equal toabout 90%, less than or equal to about 80%, less than or equal to about70%, less than or equal to about 60%, less than or equal to about 50%,less than or equal to about 40%, less than or equal to about 30%, lessthan or equal to about 20%, or less than or equal to about 10%.Combinations of the above-referenced ranges are also possible (e.g., anincrease of greater than or equal to about 10% and less than or equal toabout 90%). Other ranges are also possible. In some instances, theconcentration of a pharmaceutical agent increases at a tissue and/orfluid in the front of the eye. In other instances, the concentration ofa pharmaceutical agent increases at a tissue and/or fluid in the back ofthe eye.

The ocular concentration of a pharmaceutical agent, and, whenappropriate, its metabolite(s), in appropriate ocular fluids or tissuesmay be measured as a function of time in vivo using an appropriateanimal model. One method of determining the ocular concentration of apharmaceutical agent involves dissecting of the eye to isolate tissuesof interest (e.g., in a animal model comparable to the subject). Theconcentration of the pharmaceutical agent in the tissues of interest isthen determined by HPLC or LC/MS analysis.

In certain embodiments, the period of time between administration of theparticles described herein and obtaining a sample for measurement ofconcentration or AUC is less than about 1 hour, less than or equal toabout 2 hours, less than or equal to about 3 hours, less than or equalto about 4 hours, less than or equal to about 6 hours, less than orequal to about 12 hours, less than or equal to about 36 hours, or lessthan or equal to about 48 hours. In certain embodiments, the period oftime is at least about 1 hour, at least about 2 hours, at least about 3hours, at least about 4 hours, at least about 6 hours, at least about 8hours, at least about 12 hours, at least about 36 hours, or at leastabout 48 hours. Combinations of the above-referenced ranges are alsopossible (e.g., a period of time between consecutive doses of greaterthan or equal to about 3 hours and less than or equal to about 12hours). Other ranges are also possible.

Other methods of measuring the concentration of a pharmaceutical agentin an eye of a subject or an animal model are also possible. In someembodiments, the concentration of a pharmaceutical agent may be measuredin the eye of the subject directly or indirectly (e.g., taking a sampleof fluid, such as vitreous humor, from an eye of the subject).

In general, an increase in concentration of a pharmaceutical agent in anocular site may be calculated by taking the difference in concentrationmeasured between those of a test composition and a control composition,and dividing the difference by the concentration of the controlcomposition. A test composition may include particles comprising apharmaceutical agent, and the particles may be characterized as beingmucus penetrating (e.g., having a relative velocity of greater thanabout 0.5, or another other relative velocity described herein). Acontrol composition may include particles comprising the samepharmaceutical agent as that present in the test composition, theparticles having a substantially similar size as those of the testcomposition, but which are not mucus penetrating (e.g., having arelative velocity of less than about 0.5, or another other relativevelocity described herein).

As described herein, in some embodiments, the particles, compositions,and/or formulations described herein, or a component thereof, is presentin a sufficient amount to increase the bioavailability and/orconcentration of a pharmaceutical agent in an ocular tissue, compared tothe pharmaceutical agent administered to the ocular tissue in theabsence of the particles, compositions, and formulations describedherein, or a component thereof.

The ocular tissue may be an anterior ocular tissue (e.g., a palpebralconjunctiva, a bulbar conjunctiva, or a cornea). The pharmaceuticalagent may be any suitable agent as described herein, such as thecompounds of Formulae I-IV. In certain embodiments, the core particle ofa formulation comprising a pharmaceutical agent is present in asufficient amount to increase the bioavailability and/or concentrationof the pharmaceutical agent in an ocular tissue. In certain embodiments,the coating on the core particle of a formulation comprising apharmaceutical agent is present in a sufficient amount to increase thebioavailability and/or concentration of the pharmaceutical agent in anocular tissue. In certain embodiments, the coating on the core particleof a formulation comprising a pharmaceutical agent is present in asufficient amount to increase the concentration of the pharmaceuticalagent in an ocular tissue after at least 10 minutes, at least 20minutes, at least 30 minutes, at least 1 hour, at least 2 hours, atleast 3 hours, at least 4 hours, at least 6 hours, at least 9 hours, atleast 12 hours, at least 18 hours, or at least 24 hours afteradministration of the formulation to the ocular tissue. In certainembodiments, the coating on the core particle of a formulationcomprising a pharmaceutical agent is present in a sufficient amount toincrease the concentration of the pharmaceutical agent in an oculartissue after less than or equal to 24 hours, less than or equal to 18hours, less than or equal to 12 hours, less than or equal to 9 hours,less than or equal to 6 hours, less than or equal to 4 hours, less thanor equal to 3 hours, less than or equal to 2 hours, less than or equalto 1 hour, less than or equal to 30 minutes, less than or equal to 20minutes, or less than or equal to 10 minutes after administration of theformulation to the ocular tissue. Combinations of the above-referencedranges are also possible (e.g., the concentration of the pharmaceuticalagent increases after at least 10 minutes and less than or equal to 2hours). Other ranges are also possible. In certain embodiments, thecoating on the core particle of a formulation comprising apharmaceutical agent is present in a sufficient amount to increase theconcentration of the pharmaceutical agent in an ocular tissue afterabout 30 minutes after administration of the formulation to the oculartissue.

In some embodiments, the particles, compositions, and/or formulationsdescribed herein can be administered topically to an eye of a subject invarious forms of doses. For example, the particles, compositions, and/orformulations described herein may be administered in a single unit doseor repeatedly administered in a plurality of single unit doses. A unitdose is a discrete amount of the particles, compositions, and/orformulations described herein comprising a predetermined amount of apharmaceutical agent. In some embodiments, fewer numbers of doses (e.g.,½, ⅓, or ¼ the number doses) are required using the particles describedherein having a mucus-penetrating coating compared to particles that donot have such a coating.

The exact amount of the particles, compositions, and/or formulationsdescribed herein required to achieve a therapeutically orprophylactically effective amount will vary from subject to subject,depending, for example, on species, age, and general condition of asubject, severity of the side effects or disorder, identity of theparticular compound, mode of administration, and the like. Theparticles, compositions, and/or formulations described herein can bedelivered using repeated administrations where there is a period of timebetween consecutive doses. Repeated administration may be advantageousbecause it may allow the eye to be exposed to a therapeutically orprophylactically effective amount of a pharmaceutical agent for a periodof time that is sufficiently long for the ocular condition to betreated, prevented, or managed. In certain embodiments, the period oftime between consecutive doses is less than or equal to about 1 hour,less than or equal to about 2 hours, less than or equal to about 3hours, less than or equal to about 4 hours, less than or equal to about6 hours, less than or equal to about 12 hours, less than or equal toabout 36 hours, or less than or equal to about 48 hours. In certainembodiments, the period of time between consecutive doses is at leastabout 1 hour, at least about 2 hours, at least about 3 hours, at leastabout 4 hours, at least about 6 hours, at least about 12 hours, at leastabout 36 hours, or at least about 48 hours. Combinations of theabove-referenced ranges are also possible (e.g., a period of timebetween consecutive doses of greater than or equal to about 3 hours andless than or equal to about 12 hours). Other ranges are also possible.

Delivery of the particles, compositions, and/or formulations describedherein to an ocular tissue may result in ophthalmically efficacious druglevels in the ocular tissue for an extended period of time afteradministration (e.g., topical administration or administration by directinjection). An ophthalmically efficacious level of a drug refers to anamount sufficient to elicit the desired biological response of an oculartissue, i.e., treating an ocular disease. As will be appreciated bythose skilled in this art, the ophthalmically efficacious level of adrug may vary depending on such factors as the desired biologicalendpoint, the pharmacokinetics of the drug, the ocular disease beingtreated, the mode of administration, and the age and health of thesubject. In certain embodiments, the ophthalmically efficacious level ofa drug is an amount of the drug, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of theocular condition. The ophthalmically efficacious level of a drug canencompass a level that improves overall therapy, reduces or avoidssymptoms or causes of the ocular condition, or enhances the therapeuticefficacy of another therapeutic agent.

In some embodiments, an ophthalmically efficacious drug level may begauged, at least in part, by the maximum concentration (C_(max)) of thepharmaceutical agent in the ocular tissue after administration. In somecases, delivery of the particles, compositions, and/or formulationscomprising a pharmaceutical agent as described herein to an oculartissue may result in a higher C_(max) of the pharmaceutical agent in theocular tissue after administration, compared to marketed particles,compositions, and formulations at similar doses. In certain embodiments,the C_(max) obtained from an administration of the particles,compositions, and/or formulations described herein is at least about 3%,at least about 10%, at least about 30%, at least about 100%, at leastabout 200%, at least about 300%, at least about 400%, at least about500%, at least about 1000%, or at least about 3000%, higher than theC_(max) obtained from an administration of the marketed particles,compositions, and/or formulations. In certain embodiments, the C_(max)obtained from an administration of the particles, compositions, and/orformulations described herein is less than or equal to about 3000%, lessthan or equal to about 1000%, less than or equal to about 500%, lessthan or equal to about 400%, less than or equal to about 300%, less thanor equal to about 200%, less than or equal to about 100%, less than orequal to about 30%, less than or equal to about 10%, or less than orequal to about 3%, higher than the C_(max) obtained from anadministration of the marketed particles, compositions, and/orformulations. Combinations of the above-referenced ranges are alsopossible (e.g., an increase in C_(max) at least about 30% and less thanor equal to about 500%). Other ranges are also possible.

In some embodiments, the ophthalmically efficacious drug levels aregauged, at least in part, by minimally efficacious concentrations of thedrug, e.g., IC₅₀ or IC₉₀, as known in the art.

In certain embodiments in which ophthalmically efficacious drug levels(or C_(max), IC₅₀, or IC₉₀) are present in the ocular tissue for anextended period of time after administration, the extended period oftime after administration can range from hours to days. In certainembodiments, the extended period of time after administration is atleast 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, atleast 9 hours, at least 12 hours, at least 1 day, at least 2 days, atleast 3 days, at least 4 days, at least 5 days, at least 6 days, or atleast 1 week. In certain embodiments, the extended period of time afteradministration is less than or equal to 1 week, less than or equal to 6days, less than or equal to 5 days, less than or equal to 4 days, lessthan or equal to 3 days, less than or equal to 2 days, less than orequal to 1 day, less than or equal to 12 hours, less than or equal to 9hours, less than or equal to 6 hours, less than or equal to 4 hours,less than or equal to 2 hours, less than or equal to 1 hour.Combinations of the above-referenced ranges are also possible (e.g., anextended period of time of at least about 4 hours and less than or equalto about 1 week). Other ranges are also possible.

In certain embodiments, the particles, compositions, and/or formulationsdescribed herein may be at dosage levels sufficient to deliver aneffective amount of a pharmaceutical agent to an eye of a subject toobtain a desired therapeutic or prophylactic effect. In certainembodiments, an effective amount of a pharmaceutical agent that isdelivered to an appropriate eye tissue is at least about 10⁻³ ng/g, atleast about 10⁻² ng/g, at least about 10⁻¹ ng/g, at least about 1 ng/g,at least about 10¹ ng/g, at least about 10² ng/g, at least about 10³ng/g, at least about 10⁴ ng/g, at least about 10⁵ ng/g, or at leastabout 10⁶ ng/g of tissue weight. In certain embodiments, an effectiveamount of a pharmaceutical agent that is delivered to the eye is lessthan or equal to about 10⁶ ng/g, less than or equal to about 10⁵ ng/g,less than or equal to about 10⁴ ng/g, less than or equal to about 10³ng/g, less than or equal to about 10² ng/g, less than or equal to about10¹ ng/g, less than or equal to about 1 ng/g, less than or equal toabout 10⁻¹ ng/g, less than or equal to about 10⁻² ng/g, or less than orequal to about 10⁻³ ng/g of tissue weight. Combinations of theabove-referenced ranges are also possible (e.g., an effective amount ofa pharmaceutical agent of at least about 10⁻² ng/g and less than orequal to about 10³ ng/g of tissue weight). Other ranges are alsopossible. In certain embodiments, the particles, compositions, and/orformulations described herein may be at dosage levels sufficient todeliver an effective amount of a pharmaceutical agent to the back of aneye of a subject to obtain a desired therapeutic or prophylactic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided particles, compositions,and/or formulations to an adult. The amount to be administered to, forexample, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

The particles, compositions, and/or formulations described herein may betopically administered by any method, for example, as by drops, powders,ointments, or creams. Other topical administration approaches or formsare also possible.

In certain embodiments, the compositions and/or formulations describedherein are packaged as a ready to use shelf stable suspension. Eye dropformulations are traditionally liquid formulations (solutions orsuspensions) which can be packaged in dropper bottles (which dispense astandard drop volume of liquid) or in individual use droppers (typicallyused for preservative free drops; used once and disposed). Theseformulations are ready to use and can be self-administered. In somecases the bottle should be shaken before use to ensure homogeneity ofthe formulation, but no other preparation may be necessary. This may bethe simplest and most convenient method of ocular delivery. Thecompositions and/or formulations described herein can be packaged in thesame way as traditional eye drop formulations. They can be stored insuspension and may retain the characteristics which allow the particlesto avoid adhesion to mucus.

Methods of Preparing Particles and Pharmaceutical Compositions Thereof

In one aspect, the present invention provides methods of preparing theparticles of the invention. Methods of preparing similar particles havebeen described in U.S. patent application Ser. No. 13/886,493, filed May3, 2013, and U.S. Ser. No. 13/886,602, filed May 3, 2013, and U.S. Ser.No. 13/886,658, filed May 3, 2013, each of which is incorporated byreference herein in its entirety.

The core of the particle may be formed by any suitable method. Suitablemethods may include, for example, top-down techniques, i.e. techniquesbased on size reduction of relatively large particles into smallerparticles (e.g., milling or homogenization) or bottom-up techniques,i.e. techniques based on the growth of particles from smaller particlesor individual molecules (e.g., precipitation or spray-freezing intoliquid).

In some embodiments, the core of the particle may be coated with acoating. For example, the core may be provided or formed in a firststep, and then the core may be coated in a second step. In someembodiments, the core particle is formed and coated substantiallysimultaneously (e.g., in a single step).

In some embodiments, the particle is formed by a method that involvesusing a formulation process, a milling process, and/or a dilutionprocess. In certain embodiments, a method of forming the particleincludes a milling process, optionally with a formulation process and/ora dilution process. A formulation process may be used to form asuspension comprising a core material, one or more surface-alteringagents, and other components, such as solvents, tonicity agents,chelating agents, salts, and/or buffers (e.g., a sodium citrate andcitric acid buffer), each of which is as described herein. Theformulation process may be performed using a formulation vessel. Thecore material and other components may be added into the formulationvessel at the same time or different times. A mixture of the corematerial and/or one or more other components may be stirred and/orshaken, or otherwise agitated in the vessel to facilitate suspending thecomponents to form the suspension. The temperature and/or pressure ofthe core material, other components, and/or mixture may also beindividually increased or decreased to facilitate the suspendingprocess. In some embodiments, the core material and other components areprocessed as described herein in the formulation vessel under an inertatmosphere (e.g., nitrogen or argon) and/or protected from light. Thesuspension obtained from the formulation vessel may be subsequentlysubject to a milling process which may be followed by a dilutionprocess.

In some embodiments involving a core comprising a solid material (e.g.,crystalline compound of the invention) a milling process may be used toreduce the size of the solid material to form particles in a micrometerto nanometer size range. The milling process may be performed using amill or other suitable apparatus. Dry and wet milling processes such asjet milling, cryo-milling, ball milling, media milling, sonication, andhomogenization are known and can be used in methods of the invention.For example, in a wet milling process, a suspension of the solidmaterial to be used to form the core (“core material”) is agitated withor without excipients to reduce the size of the core to be formed. Drymilling is a process wherein the core material is mixed with millingmedia with or without excipients to reduce the size of the core to beformed. In a cyro-milling process, a suspension of the core material ismixed with milling media with or without excipients under cooledtemperatures. In certain embodiments, when surface-altering agents areemployed, a suspension comprising coated particles is obtained from themilling process. In certain embodiments, when surface-altering agentsare not employed, a suspension comprising uncoated particles is obtainedfrom the milling process.

The suspension of particles (coated or uncoated) of the inventionobtained from a milling process may be further processed with a dilutionprocess. A dilution process may be used to achieve a target dosingconcentration by diluting a suspension of particles that were formedduring a milling process, with or without surface-altering agents and/orother components. In certain embodiments, when a suspension of coatedparticles that comprise a first surface-altering agent is processed witha dilution process involving a second surface-altering agent, asuspension of coated particles that comprise the second surface-alteringagent is obtained from the dilution process. In certain embodiments,when a suspension of coated particles that comprise a surface-alteringagent is processed with a dilution process involving no or the samesurface-altering agent, a suspension of coated particles that comprisethe surface-altering agent is obtained from the dilution process. Incertain embodiments, when a suspension of uncoated particles isprocessed with a dilution process involving a surface-altering agent, asuspension of coated particles comprising the surface-altering agent isobtained from the dilution process. The dilution process may beperformed using a product vessel or any other suitable apparatus. Incertain embodiments, the suspension of the particles is diluted, i.e.,mixed or otherwise processed with a diluent, in the product vessel. Thediluent may contain solvents, surface-altering agents, tonicity agents,chelating agents, salts, anti-microbial agents or a combination thereof,as described herein. The suspension and the diluent may be added intothe product vessel at the same time or different times. In certainembodiments when the suspension is obtained from a milling processinvolving milling media, the milling media may be separated from thesuspension before the suspension is added into the product vessel. Thesuspension, the diluent, or the mixture of the suspension and thediluent may be stirred and/or shaken, or otherwise agitated, to form theparticles and/or pharmaceutical compositions of the invention. Thetemperature and/or pressure of the suspension, the diluent, or themixture may also be individually increased or decreased to form thecoated particles. In some embodiments, the suspension and the diluentare processed in the product vessel under an inert atmosphere (e.g.,nitrogen or argon) and/or protected from light.

In some embodiments, the core and/or coated particles may be produced bymilling of a solid material (e.g., a pharmaceutical agent) in thepresence of one or more surface-altering agents. Small particles of asolid material may require the presence of one or more surface-alteringagents, which may function as a stabilizer in some embodiments, in orderto stabilize a suspension of particles without agglomeration oraggregation in a liquid solution. In some such embodiments, thestabilizer may act as a surface-altering agent, forming the coatedparticles of the invention.

As described herein, a method of forming the core and/or the coatedparticles, may involve choosing a surface-altering agent that issuitable for both milling and forming a coating on the core, wherein thecoating renders the particle mucus penetrating.

In a wet milling process, milling may be performed in a dispersion(e.g., an aqueous dispersion) containing at least one surface-alteringagent, a grinding medium, a solid to be milled (e.g., a solidpharmaceutical agent), and a solvent. The solvent described hereinincludes a single solvent or a mixture of different solvents. Anysuitable amount of a surface-altering agent can be included in thesolvent. In some embodiments, the surface-altering agent may be presentin the solvent in an amount of at least about 0.001% (wt % or % weightto volume (w:v)), at least about 0.01%, at least about 0.1%, at leastabout 1%, at least about 3%, at least about 10%, at least about 30%, orat least about 60% of the solvent. In some cases, the surface-alteringagent may be present in the solvent in an amount of about 100% (e.g., inan instance where the surface-altering agent is the solvent). In otherembodiments, the surface-altering agent may be present in the solvent inan amount of less than about 100%, less than about 60%, less than about30%, less than about 10%, less than about 3%, or less than about 1% ofthe solvent. Combinations of the above-referenced ranges are alsopossible (e.g., an amount of less than about 3% and at least about 1% ofthe solvent). Other ranges are also possible. In certain embodiments,the surface-altering agent is present in the solvent in an amount ofabout 0.01-2%, about 0.2-20%, about 0.1%, about 0.4%, about 1%, about2%, about 5%, or about 10% of the solvent.

The particular range chosen may influence factors that may affect theability of the particles to penetrate mucus such as the stability of thecoating of the surface-altering agent on the particle surface, theaverage thickness of the coating of the surface-altering agent on theparticles, the orientation of the surface-altering agent on theparticles, the density of the surface altering agent on the particles,the ratio of the surface-altering agent to pharmaceutical agent, theconcentration of the pharmaceutical agent, the size, dispersibility, andpolydispersity of the particles formed, and the morphology of theparticles formed.

The pharmaceutical agent may be present in the solvent in any suitableamount. In some embodiments, the pharmaceutical agent is present in anamount of at least about 0.001% (wt % or % weight to volume (w:v)), atleast about 0.01%, at least about 0.1%, at least about 1%, at leastabout 3%, at least about 10%, at least about 30%, or at least about 60%of the solvent. In some cases, the pharmaceutical agent may be presentin the solvent in an amount of less than about 100%, less than about60%, less than about 30%, less than about 10%, less than about 3%, orless than about 1% of the solvent. Combinations of the above-referencedranges are also possible (e.g., an amount of less than about 30% and atleast about 1% of the solvent).

The ratio of surface-altering agent to pharmaceutical agent in a solventmay also vary. In some embodiments, the ratio of the surface-alteringagent to pharmaceutical agent is at least about 0.001:1 (weight ratio,molar ratio, or w:v), at least about 0.01:1, at least about 0.01:1, atleast about 1:1, at least about 2:1, at least about 3:1, at least about5:1, at least about 10:1, at least about 30:1, at least about 100:1, orat least about 1000:1. In some embodiments, the ratio of thesurface-altering agent to pharmaceutical agent is less than 1000:1(weight ratio, molar ratio, or w:v), less than about 100:1, less thanabout 30:1, less than about 10:1, less than about 5:1, less than about3:1, less than about 2:1, less than about 1:1, or less than about 0.1:1.Combinations of the above-referenced ranges are possible (e.g., a ratioof at least about 5:1 and less than about 30:1). Other ranges are alsopossible.

The surface-altering agents described herein that may act as stabilizersmay be, for example, polymers or surfactants. Examples of polymersinclude those suitable for use in the coating of the particles of theinvention, such as poly(vinyl alcohol) and Pluronics®. Examples ofsurfactants include L-α-phosphatidylcholine (PC),1,2-dipalmitoylphosphatidycholine (DPPC), oleic acid, sorbitantrioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxylenesorbitan fatty acid esters (Tweens), polysorbates (e.g., polyoxyethylenesorbitan monooleate) (e.g., Tween 80®), polyoxyethylene sorbitanmonostearate (e.g., Tween 60®), polyoxyethylene sorbitan monopalmitate(e.g., Tween 40®), polyoxyethylene sorbitan monolaurate (e.g., Tween20®), natural lecithin, oleyl polyoxyethylene ether, stearylpolyoxyethylene ether, lauryl polyoxyethylene ether, polyoxylene alkylethers, block copolymers of oxyethylene and oxypropylene,polyoxyethylene sterates, polyoxyethylene castor oil and theirderivatives, Vitamin-PEG and their derivatives, synthetic lecithin,diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate,isopropyl myristate, glyceryl monooleate, glyceryl monostearate,glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethyleneglycol, cetyl pyridinium chloride, benzalkonium chloride, olive oil,glyceryl monolaurate, corn oil, cotton seed oil, and sunflower seed oil.Derivatives of the above-noted compounds are also possible. Combinationsof the above-noted compounds and others described herein may also beused as surface-altering agents in the inventive particles. As describedherein, in some embodiments a surface-altering agent may act as astabilizer, a surfactant, and/or an emulsifier. In some embodiments, thesurface altering agent may aid particle transport in mucus.

A stabilizer used for milling may form the coating of a particle of theinvention, wherein the coating renders the particle mucus penetrating.The stabilizer may also be exchanged with one or more othersurface-altering agents after the particle has been formed. For example,a first stabilizer/surface-altering agent may be used during a millingprocess and may form a first coating of the particle of the invention,and all or part of the first stabilizer/surface-altering agent may thenbe exchanged with a second stabilizer/surface-altering agent to form asecond coating of the particle. In some embodiments, the secondstabilizer/surface-altering agent may render the particle mucuspenetrating more than the first stabilizer/surface-altering agent. Insome embodiments, a particle comprising multiple coatings that includemultiple surface-altering agents is formed by a method of the invention.

Any suitable grinding medium can be used for milling. In someembodiments, a ceramic and/or polymeric material and/or a metal can beused. Examples of suitable materials include zirconium oxide, siliconcarbide, silicon oxide, silicon nitride, zirconium silicate, yttriumoxide, glass, alumina, alpha-alumina, aluminum oxide, polystyrene,poly(methyl methacrylate), titanium, and steel. A grinding medium mayhave any suitable size. For example, the grinding medium may have anaverage diameter of at least about 0.1 mm, at least about 0.2 mm, atleast about 0.5 mm, at least about 0.8 mm, at least about 1 mm, at leastabout 2 mm, or at least about 5 mm. In some cases, the grinding mediummay have an average diameter of less than about 5 mm, less than about 2mm, less than about 1 mm, less than about 0.8, less than about 0.5 mm,or less than about 0.2 mm. Combinations of the above-referenced rangesare also possible (e.g., an average diameter of at least about 0.5millimeters and less than about 1 mm). Other ranges are also possible.

A solvent may be used for milling. The choice of the solvent suitablefor milling may depend on factors like the solid material (e.g., a solidpharmaceutical agent) being milled, the particular type ofstabilizer/surface-altering agent (e.g., one that may render theparticle mucus penetrating), and the grinding material. The solventsuitable for milling may be one of those solvents that do notsubstantially dissolve the solid material or the grinding material, butdissolve the stabilizer/surface-altering agent to a suitable degree.Examples of the solvents suitable for milling include water, aqueoussolutions, buffered solutions, alcohols (e.g., ethanol, methanol, andbutanol), and mixtures thereof, each of which may optionally includeother components, such as one or more pharmaceutical excipients,polymers, pharmaceutical agents, salts, preservative agents, viscositymodifiers, tonicity modifiers, taste masking agents, antioxidants, andpH modifiers. In some embodiments, the solvent suitable for milling isan organic solvent.

A pharmaceutical agent described herein (e.g., a compound of theinvention) may have a suitable solubility in a solvent suitable formilling, such as a solubility in one or more ranges described herein foraqueous solubility or for solubility in a coating solution. Apharmaceutical agent having a relatively low solubility in a solvent(e.g., water or a coating solution) may be preferred because a millingprocess described herein typically requires a material (e.g., apharmaceutical agent) to be in a solid form in order for the material tobe milled. In some cases, if the material to be milled has a relativelyhigh soluble in a solvent (e.g., water or a coating solution) used inthe milling process, milling may not be conducted because significant orcomplete dissolution of the material to be milled in the solvent willoccur. In certain embodiments, a relatively high solubility of a solidmaterial (e.g., a solid pharmaceutical agent) in a solvent is at leastabout 1 mg/mL, at least about 3 mg/mL, or at least about 10 mg/mL at 25°C. In certain embodiments, a relatively low solubility of a substance(e.g., a pharmaceutical agent) in a solvent is less than about 1 mg/mL,less than about 0.3 mg/mL, less than about 0.1 mg/mL, less than about0.03 mg/mL, less than about 0.01 mg/mL, less than about 0.003 mg/mL, orless than about 0.001 mg/mL at 25° C. The solid material may have theseor other ranges of solubilities at any point throughout the pH range(e.g., from pH 1 to pH 14). A pharmaceutical agent that has a relativelyhigh solubility in the solvent used in the milling process may bemodified to form a prodrug of the pharmaceutical agent. The prodrug mayhave a relatively low solubility and thus may be suitable for themilling process. Upon or after the particles or pharmaceuticalcompositions comprising the prodrug are administered to a subject, theprodrug may be converted and form or, in other words, “release,” thepharmaceutical agent.

In other embodiments, the core and/or coated particles may be formed byan emulsification process or technique (emulsification) known in theart. See, e.g., U.S. patent application Ser. No. 13/886,602. Generally,emulsification techniques may involve dissolving or dispersing amaterial to be used as the core in a solvent; this solution ordispersion is then emulsified in a second immiscible solvent, therebyforming a plurality of particles comprising the material. Suitableemulsification techniques may include formation of oil-in-wateremulsions, water-in-oil emulsions, water-oil-water emulsions,oil-water-oil emulsions, solid-in-oil-in-water emulsions, andsolid-in-water-in-oil emulsions, etc., with or without subsequentsolvent removal, for example, by evaporation or extraction.Emulsification techniques are versatile and may be useful for preparingcore particles comprising pharmaceutical agents having a relatively lowaqueous solubility as well as pharmaceutical agents having a relativelyhigh aqueous solubility.

In some embodiments, the core particles described herein may be producedby emulsification in the presence of one or more surface-alteringagents. In some such embodiments, the stabilizer may act as asurface-altering agent, forming a coating on the particle (i.e., theemulsification and coating steps may be performed substantiallysimultaneously).

In some embodiments, a method of forming a core particle byemulsification involves choosing a stabilizer that is suitable for bothemulsification and for forming a coating on the particle and renderingthe particle mucus penetrating. For example, as described in more detailbelow, it has been demonstrated that 200-500 nm nanoparticles of a modelpolymer PLA produced by emulsification in the presence of certain PVApolymers resulted in particles that can penetrate physiological mucussamples at the same rate as well-established PEGylated polymeric MPP.Interestingly, it was observed that only a subset of PVA polymers testedfit the criteria of being suitable for both emulsification and forforming a coating on the particle that renders the particle mucuspenetrating, as described in more detail below.

In other embodiments, the particles are first formed using anemulsification technique, following by coating of the particles with asurface-altering agent.

Any suitable solvent and solvent combinations can be used foremulsification. Some examples of solvents which can serve as oil phaseare organic solvents such chloroform, dichloromethane, ethyl acetate,ethyl ether, petroleum ether (hexane, heptane), and oils such as peanutoil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oilsoybean oil, and silicone oil. Some examples of solvents which can serveas water phase are water and aqueous buffers. Other solvents are alsopossible.

The core and/or coated particles may also be formed by a precipitationprocess or technique (precipitation). Precipitation techniques (e.g.,microprecipitation, nanoprecipitation, crystallization, and controlledcrystallization) may involve forming a first solution comprising thematerial that is to form the core (e.g., a pharmaceutical agent) and afirst solvent, wherein the material has a relatively high solubility inthe first solvent. The first solution may be added to a second solutioncomprising a second solvent that is an anti-solvent, in which thematerial has a relatively low solubility, thereby forming a plurality ofparticles comprising the material. In certain embodiments, the secondsolvent is miscible with the first solvent. In some embodiments, one ormore surface-altering agents and/or surfactants may be present in thefirst and/or second solutions. A coating may be formed during theprocess of precipitating the core (e.g., the coating of the particlesmay be formed substantially simultaneously when the precipitation isperformed) to form the coated particles of the invention.

In other embodiments, the core of the particles of the invention isfirst formed using a precipitation technique, following by coating ofthe core with a surface-altering agent to form the coated particles ofthe invention.

In some embodiments, a precipitation technique may be used to formpolymeric core of the particles of the invention with or without apharmaceutical agent. Generally, a precipitation technique involvesdissolving a polymer that is to form the core in a first solvent, in thepresence or absence of a pharmaceutical agent, to form a solution. Thesolution is then added to a second solvent that is an anti-solvent andis miscible with the first solvent, in the presence or absence of one ormore excipients, to form the core of the particles. In some embodiments,precipitation is useful for preparing a polymeric core comprising one ormore pharmaceutical agents having a relatively low aqueous solubility.

The precipitation described herein involves the use of a first solvent.Examples of suitable first solvents for precipitation include organicsolvents (e.g., acetone, acetonitrile, dimethylformamide,dimethysulfoxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, andtetrahydrofuran) and nonorganic solvents.

The precipitation described herein also involves the use of a secondsolvent. In certain embodiments, the second solvent suitable forprecipitation is an anti-solvent. Examples of second solvents suitablefor precipitation include the solvents described herein that may be usedfor milling. In some embodiments, the second solvents suitable forprecipitation is water, an aqueous solution (e.g., a buffered solution),an alcohol (e.g., methanol, ethanol, propanol, or butanol), or a mixturethereof, optionally including one or more other components, such aspharmaceutical excipients, polymers, and pharmaceutical agents.

Surface-altering agents for the emulsification and precipitationdescribed herein may be polymers or surfactants, including thesurface-altering agents described herein that may be used for milling.

Examples of polymers suitable for forming all or part of the core of theparticles of the invention by the emulsification or precipitation mayinclude polyamines, polyethers, polyamides, polyesters, polycarbamates,polyureas, polycarbonates, polystyrenes, polyimides, polysulfones,polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines,polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles,polyarylates, polypeptides, polynucleotides, and polysaccharides.Non-limiting examples of specific polymers include poly(caprolactone)(PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA),poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lacticacid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid)(PLLGA), poly(D,L-lactide) (PDLA), poly(L-lactide) (PLLA),poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-caprolactone-co-glycolide),poly(D,L-lactide-co-PEO-co-D,L-lactide),poly(D,L-lactide-co-PPO-co-D,L-lactide), polyalkyl cyanoacrylate,polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA),poly(ethylene glycol), poly-L-glutamic acid, poly(hydroxy acids),polyanhydrides, polyorthoesters, poly(ester amides), polyamides,poly(ester ethers), polycarbonates, polyalkylenes such as polyethyleneand polypropylene, polyalkylene glycols such as poly(ethylene glycol)(PEG), polyalkylene oxides (PEO), polyalkylene terephthalates such aspoly(ethylene terephthalate), polyvinyl alcohols (PVA), polyvinylethers, polyvinyl esters such as poly(vinyl acetate), polyvinyl halidessuch as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxanes,polystyrene (PS), polyurethanes, derivatized celluloses such as alkylcelluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters,nitro celluloses, hydroxypropylcellulose, carboxymethylcellulose,polymers of acrylic acids, such as poly(methyl(meth)acrylate) (PMMA),poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate),poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate),poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate),poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropylacrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) (jointlyreferred to herein as “polyacrylic acids”), and copolymers and mixturesthereof, polydioxanone and its copolymers, polyhydroxyalkanoates,polypropylene fumarate), polyoxymethylene, poloxamers,poly(ortho)esters, poly(butyric acid), poly(valeric acid),poly(lactide-co-caprolactone), and trimethylene carbonate,polyvinylpyrrolidone, bovine serum albumin, human serum albumin,collagen, DNA, RNA, carboxymethyl cellulose, chitosan, dextran.

Polymers suitable for forming all or portions of a core and/orsurface-altering agent may also include a poly(ethylene glycol)-vitaminE conjugate (hereinafter, “PEG-VitE conjugate”). The particles,compositions, and/or formulations including a PEG-VitE conjugate, andmethods of making and using the particles, compositions, and/orformulations, are provided in more detail in international PCTapplication publication WO2012/061703, which is incorporated herein byreference in its entirety for all purposes. In some cases, the molecularweight of the PEG portion of the PEG-VitE conjugate is greater thanabout 2 kDa. The molecular weight of the PEG portion of the PEG-VitEconjugate may be selected so as to aid in the formation and/or transportof the particle across a mucosal barrier as described herein. In someembodiments, use of a PEG-VitE conjugate with a PEG portion having amolecular weight greater than about 2 kDa may allow for greaterpenetration of the particles through a mucosal barrier as compared touse of a PEG-VitE conjugate with a PEG portion having a molecular weightless than about 2 kDa. Additionally, in certain embodiments a highermolecular weight PEG portion may facilitate drug encapsulation. Thecombined ability to act as a surfactant and to reduce mucoadhesionprovides important benefits as compared to other commonly usedsurfactants for drug encapsulation. In some cases, the molecular weightof the PEG portion of the PEG-VitE conjugate is between about 2 kDa andabout 8 kDa, or between about 3 kDa and about 7 kDa, or between about 4kDa and about 6 kDa, or between about 4.5 kDa and about 6.5 kDa, orabout 5 kDa.

In some embodiments, a precipitation technique may be used to formparticles comprised predominantly of a pharmaceutical agent (e.g., acompound of the invention). In certain embodiments, the particles of theinvention formed by the precipitation technique comprise predominantlyof a pharmaceutical agent that is a nanocrystal. Generally, such aprecipitation technique involves dissolving the pharmaceutical agentthat is to form the core in a first solvent, which is then added to asecond solvent that is an anti-solvent, in which the pharmaceuticalagent has a relatively low solubility, in the presence or absence of oneor more pharmaceutical excipients, to form the core or uncoatedparticle. In some embodiments, this technique may be useful forpreparing, for example, particles of pharmaceutical agents that areslightly soluble (1-10 mg/mL), very slightly soluble (0.1-1 mg/mL) orpractically insoluble (<0.1 mg/mL) in aqueous solutions (e.g., agentshaving a relatively low aqueous solubility).

A pharmaceutical agent described herein (e.g., a compound of theinvention) may have a suitable solubility in the first and secondsolvents suitable for precipitation, such as a solubility in one or moreranges described herein for aqueous solubility or for solubility in acoating solution. A pharmaceutical agent having a relatively highsolubility in the first solvent (e.g., an organic solvent) may bepreferred. In certain embodiments, the pharmaceutical agentsubstantially or completely dissolves in the first solvent. Apharmaceutical agent having a relatively low solubility in the secondsolvent (e.g., water or a coating solution) may also be preferred. Incertain embodiments, the solubility of the pharmaceutical agent in amixture of the first and second solvents is lower than the solubility ofthe pharmaceutical agent in the first solvent. The relatively highsolubility and relatively low solubility are as described herein. Apharmaceutical agent that has a relatively high solubility in the secondsolvent may be modified to form a prodrug of the pharmaceutical agent.The prodrug may have a relatively low solubility in the second solventand still have a relatively high solubility in the first solvent andthus may be suitable for precipitation. Upon or after the particles orpharmaceutical compositions comprising the prodrug are administered to asubject, the prodrug may be converted and form or, in other words,“release,” the pharmaceutical agent.

Precipitation by formation of a salt or complex may also be used to formparticles comprised predominantly of a salt or complex of apharmaceutical agent. In certain embodiments, the particles formed bythis specific precipitation technique comprise predominantly of apharmaceutical agent that is a nanocrystal. Generally, precipitation byformation of a salt or complex involves dissolving a pharmaceuticalagent that is to form the core in a solvent, in the presence or absenceof one or more excipients, followed by the addition of a counterion or acomplexing agent, which forms a salt or a complex with thepharmaceutical agent to form the core. A variety of counter-ions can beused to form salt complexes, including metals (e.g., alkali metals,alkali earth metals and transition metals). Non-limiting examples ofcationic counter-ions include zinc, calcium, aluminum, zinc, barium, andmagnesium. Non-limiting examples of anionic counter-ions includephosphate, carbonate, and fatty acids. Counter-ions may be, for example,monovalent, divalent, or trivalent. Other counter-ions are known in theart and can be used in the embodiments described herein. Other ionic andnon-ionic complexing agents are also possible. This technique may beuseful for preparing particles comprising pharmaceutical agents thathave a relatively high solubility in the second solvent (e.g., water ora coating solution). In certain embodiments, the pharmaceutical agenthas a relatively high solubility in the second solvent, and the salt orcomplex of the pharmaceutical agent has a relatively low solubility inthe second solvent. The relatively high solubility and relatively lowsolubility are as described herein. In some embodiments, pharmaceuticalagents having one or more charged or ionizable groups interact with acounterion (e.g., a cation or an anion) to form a salt or complex.

A variety of different acids may be used in a precipitation processinvolving formation of a salt or complex. Examples of acids suitable forprecipitation include deconoic acid, hexanoic acid, mucic acid, octanoicacid. In other embodiments, a suitable acid may include acetic acid,adipic acid, L-ascorbic acid, L-aspartic acid, capric acid (decanoicacid), carbonic acid, citric acid, fumaric acid, galactaric acid,D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid,glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid,hydrochloric acid, DL-lactic acid, lauric acid, maleic acid, (−)-L-malicacid, palmitic acid, phosphoric acid, sebacic acid, stearic acid,succinic acid, sulfuric acid, (+)-L-tartaric acid, or thiocyanic acid.In other embodiments, a suitable acid may include alginic acid,benzenesulfonic acid, benzoic acid, (+)-camphoric acid, caprylic acid(octanoic acid), cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, ethanesulfonic acid,2-hydroxy-, gentisic acid, glutaric acid, 2-oxo-, isobutyric acid,lactobionic acid, malonic acid, methanesulfonic acid,naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,2-naphthoic acid, 1-hydroxy-, nicotinic acid, oleic acid, orotic acid,oxalic acid, pamoic acid, (embonic acid), propionic acid,(−)-L-pyroglutamic acid, or p-toluenesulfonic acid. In yet otherembodiments, a suitable acid may include acetic acid, 2,2-dichloro-,benzoic acid, 4-acetamido-, (+)-camphor-10-sulfonic acid, caproic acid(hexanoic acid), cinnamic acid, formic acid, hydrobromic acid,DL-mandelic acid, nitric acid, salicylic acid, salicylic acid, 4-amino-,and undecylenic acid (undec-10-enoic acid). Mixtures of two or moreacids can also be used.

A variety of different bases may also be used in a precipitation processinvolving formation of a salt or complex. Examples of bases suitable forprecipitation include ammonia, L-arginine, calcium hydroxide, choline,glucamine, N-methyl-, lysine, magnesium hydroxide, potassium hydroxide,or sodium hydroxide. In other embodiments, a suitable base may includebenethamine, benzathine, betaine, deanol, diethylamine, ethanol,2-(diethylamino)-, hydrabamine, morpholine, 4-(2-hydroxyethyl)-,pyrrolidine, 1-(2-hyroxyethyl)-, or tromethamine. In other embodiments,a suitable base may include diethanolamine (2,2′-iminobis(ethanol)),ethanolamine (2-aminoethanol), ethylenediamine, 1H-imidazole,piperazine, triethanolamine (2,2′,2″-nitrilotris(ethanol)), and zinchydroxide. Mixtures of two or more bases can also be used.

Examples of solvents suitable for precipitation involving formation of asalt or complex include the solvents described herein that may be usedfor milling. In some embodiments, the first or second solvent suitablefor precipitation involving formation of a salt or complex is water, anaqueous solution (e.g., a buffered solution), an alcohol (e.g.,methanol, ethanol, propanol, or butanol), or a mixture thereof,optionally including one or more other components, such aspharmaceutical excipients, polymers, and pharmaceutical agents.

The first or second solvent suitable for precipitation may include oneor more surface-altering agents as described herein, and therefore, acoating comprising the one or more surface-altering agents may be formedaround the core to provide the coated particles of the invention as theyprecipitate out of solution. The one or more surface-altering agents maybe present in the first or second solvent at any suitable concentration,such as a concentration of at least about 0.001% (w/v), at least about0.003% (w/v), at least about 0.01% (w/v), at least about 0.03% (w/v), atleast about 0.1% (w/v), at least about 0.3% (w/v), at least about 1%(w/v), or at least about 3% (w/v). In some embodiments, the one or moresurface-altering agents are present in the first or second solvent at aconcentration of less than about 3% (w/v), less than about 1% (w/v),less than about 0.3% (w/v), less than about 0.1% (w/v), less than about0.05% (w/v), less than about 0.01% (w/v), or less than about 0.003%(w/v). Combinations of the above-referenced ranges are also possible(e.g., a concentration of at least about 0.01 (w/v) and less than about1% (w/v). Other ranges are also possible. In certain embodiments, theone or more surface-altering agents are present in the first solvent butabsent in the second solvent. In certain embodiments, the one or moresurface-altering agents are present in the second solvent but absent inthe first solvent. In certain embodiments, the one or moresurface-altering agents are present in both the first and secondsolvents.

In the precipitation process, the salt may have a lower aqueoussolubility (or solubility in the solvent containing the salt) than thepharmaceutical agent in the non-salt form. The aqueous solubility (orsolubility in the solvent) of the salt may be, for example, less than orequal to about 5 mg/mL, less than or equal to about 2 mg/mL, less thanor equal to about 1 mg/mL, less than or equal to about 0.5 mg/mL, lessthan or equal to about 0.1 mg/mL, less than or equal to about 0.05mg/mL, or less than or equal to about 0.01 mg/mL, less than or equal toabout 1 g/mL, less than or equal to about 0.1 μg/mL, less than or equalto about 0.01 g/mL, less than or equal to about 1 ng/mL, less than orequal to about 0.1 ng/mL, or less than or equal to about 0.01 ng/mL at25° C. In some embodiments, the salt may have an aqueous solubility (orsolubility in the solvent) of at least about 1 pg/mL, at least about 10pg/mL, at least about 0.1 ng/mL, at least about 1 ng/mL, at least about10 ng/mL, at least about 0.1 g/mL, at least about 1 g/mL, at least about5 g/mL, at least about 0.01 mg/mL, at least about 0.05 mg/mL, at leastabout 0.1 mg/mL, at least about 0.5 mg/mL, at least about 1.0 mg/mL, atleast about 2 mg/mL. Combinations of the above-noted ranges are possible(e.g., an aqueous solubility (or solubility in the solvent) of at leastabout 0.001 mg/mL and less than or equal to about 1 mg/mL). Other rangesare also possible. The salt may have these or other ranges of aqueoussolubilities at any point throughout the pH range (e.g., from pH 1 to pH14).

Another exemplary method of forming the core and/or coated particle is afreeze-drying process or technique known in the art. See, e.g., U.S.patent application Ser. No. 13/886,602. In this technique, apharmaceutical agent or salt thereof may be dissolved in an aqueoussolution, optionally containing a surface-altering agent. A counter-ionmay be added to the solution, and the solution may be immediately flashfrozen and freeze dried. Dry powder can be reconstituted in a suitablesolvent (e.g., an aqueous solution such as water) at a desiredconcentration.

A counter-ion may be added to a solvent for freeze-drying in anysuitable range. In some cases, the ratio of counter-ion topharmaceutical agent (e.g., salt) may be at least 0.1:1 (weight ratio ormolar ratio), at least 1:1, at least 2:1, at least 3:1, at least 5:1, atleast 10:1, at least 25:1, at least 50:1, or at least 100:1. In somecases, the ratio of counter-ion to pharmaceutical agent (e.g., salt) maybe less than or equal to 100:1 (weight ratio or molar ratio), less thanor equal to 75:1, less than or equal to 50:1, less than or equal to25:1, less than or equal to 10:1, less than or equal to 5:1, less thanor equal to 3:1, less than or equal to 2:1, less than or equal to 1:1,or less than or equal to 0.1:1. Combinations of the above-referencedranges are possible (e.g., a ratio of at least 5:1 and less than orequal to 50:1). Other ranges are also possible.

If the surface-altering agent is present in the solvent prior to freezedrying, it may be present at any suitable concentration, such as aconcentration of at least about 0.001% (w/v), at least about 0.005%(w/v), at least about 0.01% (w/v), at least about 0.05% (w/v), at leastabout 0.1% (w/v), at least about 0.5% (w/v), at least about 1% (w/v), orat least about 5% (w/v) in the aqueous solution. In some instances, thesurface-altering agent is present in the solvent at a concentration ofless than or equal to about 5% (w/v), less than or equal to about 1%(w/v), less than or equal to about 0.5% (w/v), less than or equal toabout 0.1% (w/v), less than or equal to about 0.05% (w/v), less than orequal to about 0.01% (w/v), or less than or equal to about 0.005% (w/v).Combinations of the above-referenced ranges are also possible (e.g., aconcentration of at least about 0.01% (w/v) and less than or equal toabout 1% (w/v). Other ranges are also possible.

The concentration of surface-altering agent present in the solvent maybe above or below the critical micelle concentration (CMC) of thesurface-altering agent, depending on the particular surface-alteringagent used. In other embodiments, stable particles can be formed byadding excess counter-ion to a solution containing a pharmaceuticalagent. The precipitate can then be washed by various methods such ascentrifugation. The resultant slurry may be sonicated. One or moresurface-altering agents may be added to stabilize the resultantparticles.

Other methods of forming core particles are also possible. For example,additional techniques of forming the core and/or coated particlesinclude coacervation-phase separation, melt dispersion, interfacialdeposition, in situ polymerization, self-assembly of macromolecules(e.g., formation of polyelectrolyte complexes orpolyelectrolyte-surfactant complexes), spray-drying andspray-congealing, electro-spray, air suspension coating, pan and spraycoating, freeze-drying, air drying, vacuum drying, fluidized-bed drying,precipitation (e.g., nanoprecipitation, microprecipitation), criticalfluid extraction, and lithographic approaches (e.g., soft lithography,step and flash imprint lithography, interference lithography, andphotolithography). Combinations of the methods described herein are alsopossible. In some embodiments, a core of a pharmaceutical agent is firstformed by precipitation, and then the size of the core is reduced by amilling process, optionally a coating is form on the core by the millingprocess.

Following the formation of the core of the particles including apharmaceutical agent, the core may be optionally exposed to a solutioncomprising a (second) surface-altering agent that may associate withand/or coat the core. In embodiments in which the pharmaceutical agentalready includes a coating of a first surface-altering agent, all orpart of the first surface-altering agent may be exchanged with a secondsurface-altering agent. In some embodiments, the second surface-alteringagent renders the particle mucus penetrating more than the firstsurface-altering agent does. In some embodiments, a particle having acoating including multiple surface-altering agents is formed (e.g., in asingle layer or in multiple layers). In some embodiments, a particlehaving multiple coatings (e.g., each coating optionally comprisingdifferent surface-altering agents) may be formed. In some embodiments,the coating is in the form of a monolayer of a surface-altering agent.Other configurations are also possible.

In any of the methods described herein, a coating comprising asurface-altering agent may be formed on a core of the particles of theinvention by incubating the core in a solution including thesurface-altering agent for a period of at least about 1 minute, at leastabout 3 minutes, at least about 10 minutes, at least about 20 minutes,at least about 30 minutes, at least about 60 minutes, or more. In somecases, incubation may take place for a period of less than about 10hours, less than about 3 hours, or less than about 60 minutes.Combinations of the above referenced ranges are also possible (e.g., anincubation period of less than 60 minutes and at least about 1 minute).

Methods of Treatment and Uses

A range of diseases may result when the body of a subject loses controlover angiogenesis, i.e., new blood vessels grow abnormally (i.e.,excessively or insufficiently) or grow as a result of a tumor. Excessiveangiogenesis is often observed in subjects with diseases such asproliferative diseases (e.g., cancers, benign neoplasms, inflammatorydiseases, autoimmune diseases) and ocular diseases, especially withcancer, diabetic retinopathy, macular degeneration, rheumatoidarthritis, and psoriasis. In these diseases, new blood vessels feedabnormal tissues and/or destroy normal tissues. Excessive angiogenesismay occur when there are abnormal amounts of angiogenic growth factorspresent, overwhelming the effects of natural angiogenesis inhibitors.Therefore, inhibiting new blood vessel growth may be useful to treatdiseases associated with excessive angiogenesis. Insufficientangiogenesis is typically observed in subjects with a disease such ascoronary artery disease, stroke, or chronic wounds. In these diseases,blood vessel growth is inadequate, and circulation is not properlyrestored, which may lead to tissue death.

VEGFs have been found to play a major role in angiogenesis, for example,by increasing the number of capillaries in a given network. In vitrostudies have demonstrated that bovine capillary endothelial cellsproliferated and showed signs of tube structures upon stimulation withVEGF. Upregulation of VEGF is a major component of the physiologicalresponse to exercise and its role in angiogenesis is suspected to be apossible treatment in vascular injuries. In vitro studies have showedthat VEGFs are a potent stimulator of angiogenesis because, among otherthings, in the presence of this growth factor, plated endothelial cellswill proliferate and migrate, eventually forming tube structuresresembling capillaries. VEGFs may cause a massive signaling cascade inendothelial cells. Binding to VEGF receptor-2 starts a tyrosine kinasesignaling cascade that stimulates the production of factors thatvariously stimulate vessel permeability, proliferation/survival,migration, and finally differentiation into mature blood vessels.Mechanically, VEGF is upregulated with muscle contractions as a resultof increased blood flow to affected areas. The increased flow alsocauses a large increase in the mRNA production of VEGF receptors 1 and2. The increase in receptor production indicates that musclecontractions could cause upregulation of the signaling cascade relatingto angiogenesis.

In one aspect, the present invention provides methods of treating and/orpreventing a disease associated with abnormal angiogenesis in a subjectin need thereof. In certain embodiments, the disease being treatedand/or prevented by the inventive methods is associated with excessiveand/or pathological angiogenesis.

In another aspect, the present invention provides methods of treatingand/or preventing a disease associated with aberrant signaling of agrowth factor in a subject in need thereof. In certain embodiments, thedisease is associated with excessive signaling of the growth factor. Incertain embodiments, the disease being treated and/or prevented by theinventive methods is associated with aberrant signaling of VEGF. Incertain embodiments, the disease is associated with excessive oraberrant signaling of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-F, and/orplacental growth factor (PGF).

In certain embodiments, the disease being treated and/or prevented bythe inventive methods is a proliferative disease. All types ofproliferative diseases described herein may be treated and/or preventedby the inventive methods. In certain embodiments, the disease beingtreated and/or prevented by the inventive methods is cancer. All typesof cancer described herein may be treated and/or prevented by theinventive methods. In certain embodiments, the cancer is an ocularcancer. In certain embodiments, the ocular cancer is retinoblastoma,medulloepithelioma, uveal melanoma, ciliary body melanoma, or primaryintraocular lymphoma. In certain embodiments, the disease being treatedand/or prevented by the inventive methods is a benign neoplasm. Alltypes of benign neoplasm described herein may be treated and/orprevented by the inventive methods. In certain embodiments, the benignneoplasm is an ocular benign neoplasm. In certain embodiments, thebenign neoplasm is orbital dermoid cysts.

In certain embodiments, the disease being treated and/or prevented bythe inventive methods is an inflammatory disease. All types ofinflammatory diseases described herein may be treated and/or preventedby the inventive methods. In certain embodiments, the inflammatorydisease is an ocular inflammatory disease. In certain embodiments, theocular inflammatory disease is post-surgical inflammation. In certainembodiments, the disease being treated and/or prevented by the inventivemethods is an autoimmune disease. All types of autoimmune diseasesdescribed herein may be treated and/or prevented by the inventivemethods. In certain embodiments, the autoimmune disease is rheumatoidarthritis. In certain embodiments, the disease being treated and/orprevented by the inventive methods is diabetes. In certain embodiments,the disease is type 1 diabetes. In certain embodiments, the disease istype 2 diabetes. In certain embodiments, the disease is gestationaldiabetes.

The disease being treated and/or prevented by the inventive methods maybe an ocular disease. In some embodiments, the ocular disease beingtreated and/or prevented by the inventive methods is an anterior oculardisease that occurs at the anterior portion or “front” of the eye of asubject. The anterior portion of the eye includes the cornea, iris,conjunctiva, tear film, corneal epithelium, anterior chamber, lens,ciliary body, ciliary zonule, posterior chamber, retina, macula, sclera,an optic nerve, choroid, and vitreous chamber. In certain embodiments,the anterior ocular disease being treated and/or prevented by theinventive methods is allergy, post-surgical inflammation, uveitis, aninfection (e.g., a viral, bacterial, or fungal infection), aphakia,pseudophakia, astigmatism, blepharospasm, cataract, a conjunctivaldisease, conjunctivitis, a corneal disease, corneal oedema, meibomiamgland disease, corneal transplant surgery, corneal ulcer, dry eye (e.g.,dry eye syndrome), an eyelid disease, a lacrimal apparatus disease,lacrimal duct obstruction, laser induced exudation, myopia, presbyopia,pterygium, pupil disorders, corneal neovascularization, a refractivedisorder, strabismus, or glaucoma. In some embodiments, the oculardisease being treated and/or prevented by the inventive methods is aposterior ocular disease that occurs at the posterior portion or “back”of the eye. The posterior portion of the eye includes the choroid,sclera, vitreous humor, vitreous chamber, retina, macula, optic nerve,and blood vessels and nerves which vascularize or innervate a posteriorocular region or site. In certain embodiments, the posterior oculardisease being treated and/or prevented by the inventive methods isintraocular melanoma, acute macular neuroretinopathy, an exudative eyedisease, Behcet's disease, exudative retinopathy, macular oedema,retinopathy of prematurity, an epiretmal membrane disorder, choroidalneovascularization, uveitis, diabetic uveitis, histoplasmosis, aninfection (e.g., a viral, bacterial, or fungal infection), maculardegeneration (e.g., acute macular degeneration and age-related maculardegeneration (AMD, such as non-exudative age-related maculardegeneration and exudative age-related macular degeneration)), edema(e.g., macular edema, such as cystoid macular edema (CME) and diabeticmacular edema (DME)), multifocal choroiditis, ocular trauma whichaffects a posterior ocular site or location, ocular cancer, a retinaldisorder (e.g., central retinal vein occlusion), diabetic retinopathy(e.g., proliferative diabetic retinopathy and non-proliferative diabeticretinopathy), proliferative vitreoretinopathy (PVR), retinal arterialocclusive disease, retinal detachment, uveitic retinal disease,sympathetic opthalmia, Vogt Koyanagi-Harada (VKH) syndrome, uvealdiffusion, a posterior ocular condition caused by or influenced by anocular laser treatment, a posterior ocular condition caused by orinfluenced by a photodynamic therapy, photocoagulation, radiationretinopathy, an epiretinal membrane disorder, branch retinal veinocclusion, anterior ischemic optic neuropathy, non-retinopathy diabeticretinal dysfunction, retinitis pigmentosa, retinoblastoma, or glaucoma.In certain embodiments, the ocular disease being prevented and/ortreated by the inventive methods is macular degeneration. In certainembodiments, the ocular disease is age-related macular degeneration(AMD). In certain embodiments, the ocular disease is glaucoma. Incertain embodiments, the ocular disease is diabetic retinopathy. Incertain embodiments, the ocular disease is retinoblastoma. In certainembodiments, the ocular disease is edema. In certain embodiments, theocular disease is cystoid macular edema (CME). In certain embodiments,the ocular disease is diabetic macular edema (DME). In certainembodiments, the ocular disease is an ocular inflammatory disease. Incertain embodiments, the ocular disease is post-surgical inflammation.In certain embodiments, the ocular disease is uveitis (e.g., anterioruveitis, intermediate uveitis, and posterior uveitis). In certainembodiments, the ocular disease is blepharitis. In certain embodiments,the ocular disease is panuveitis. In certain embodiments, the oculardisease is scleritis. In certain embodiments, the ocular disease is dryeye. In certain embodiments, the ocular disease is Sjögren's syndrome.In certain embodiments, the ocular disease is an eye surgery.

Another aspect of the present invention relates to methods of inhibitingthe aberrant signaling of a growth factor signaling pathway (e.g., VEGF)in a subject or cell.

In another aspect, the present invention provides methods of inhibitingabnormal or pathological angiogenesis in a subject in need thereof.

In certain embodiments, the subject described herein is a human. Incertain embodiments, the subject is an animal. The animal may be ofeither sex and may be at any stage of development. In certainembodiments, the subject is a fish. In certain embodiments, the subjectis a mammal. In certain embodiments, the subject is a domesticatedanimal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a companion animal such as a dog or cat. Incertain embodiments, the subject is a livestock animal such as a cow,pig, horse, sheep, or goat. In certain embodiments, the subject is a zooanimal. In another embodiment, the subject is a research animal such asa rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certainembodiments, the animal is a genetically engineered animal. In certainembodiments, the animal is a transgenic animal.

In certain embodiments, the cell described herein is in vivo. In certainembodiments, the cell is in vitro. In certain embodiments, the cell isex vitro.

In certain embodiments, the methods of the invention includeadministering to a subject in need thereof an effective amount of acompound, particle, or pharmaceutical composition of the invention. Incertain embodiments, the methods of the invention include contacting acell with an effective amount of a compound, particle, or pharmaceuticalcomposition of the invention.

In certain embodiments, the inventive methods are in vivo methods. Incertain embodiments, the inventive methods are in vitro methods. Incertain embodiments, the inventive methods are ex vitro methods.

Another aspect of the invention relates to methods of screening alibrary of compounds to identify one or more compounds that are usefulin the methods of the invention. In certain embodiments, the one or morecompounds identified are useful for treating and/or preventing a diseaseassociated with abnormal or pathological angiogenesis in a subject inneed thereof. In certain embodiments, the one or more compoundsidentified are useful for treating and/or preventing a diseaseassociated with aberrant signaling of a growth factor in a subject inneed thereof. In certain embodiments, the one or more compoundsidentified are useful for inhibiting abnormal or pathologicalangiogenesis in a subject in need thereof. In certain embodiments, theone or more compounds identified are useful for inhibiting aberrantsignaling of a growth factor in a subject or cell in need thereof. Incertain embodiments, the library of compounds is a library of compoundsof the invention. In certain embodiments, the methods of screening alibrary include providing at least two different compounds of theinvention; and performing at least one assay using the differentcompounds of the invention, to identify one or more compounds that areuseful in the inventive methods.

Typically, the methods of screening a library of compounds involve atleast one assay. In certain embodiments, the assay is performed todetect one or more characteristics associated with the treatment and/orprevention of a disease described herein, with the inhibition ofabnormal angiogenesis, and/or with the inhibition of aberrant signalingof a growth factor. The characteristics may be desired (e.g., a diseasebeing treated or prevented, abnormal angiogenesis being inhibited, oraberrant signaling of a growth factor being inhibited) or undesired(e.g., a disease not being treated or prevented, abnormal angiogenesisnot being inhibited, or aberrant signaling of a growth factor not beinginhibited) characteristics. The assay may be an immunoassay, such as asandwich-type assay, competitive binding assay, one-step direct test,two-step test, or blot assay. The step of performing at least one assaymay be performed robotically or manually.

In another aspect, the present invention provides the compounds,particles, and pharmaceutical compositions of the invention for use inthe treatment and/or prevention of a disease described herein in asubject in need thereof.

In yet another aspect, the present invention provides the compounds,particles, and pharmaceutical compositions of the invention for use inthe inhibition of abnormal angiogenesis in a subject in need thereof.

In still another aspect, the present invention provides the compounds,particles, and pharmaceutical compositions of the invention for use inthe inhibition of aberrant signaling of a growth factor in a subject orcell in need thereof.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

General Preparation of the Compounds

Compounds of Formula (I) may be prepared by the synthetic sequencesoutlined below in Schemes 1 and 2, wherein X, Y, Ring A, Ring Y, R^(A),R^(B), R^(C), R^(D), R^(L), a, l, and m are as defined herein, and eachone of LG¹ to LG³ is independently a leaving group as described herein.Alternatively, compounds of Formula (I) may be prepared by other methodsdescribed herein or known in the art.

In Scheme 1, the starting point of the synthesis compounds of Formula(I) is compounds of Formula 1. Synthesis of compounds of Formula 1, suchas compound 6 (below), is known in the art. See, e.g., international PCTapplication publication, WO 2008/016192; Okaniwa et al., Journal ofMedicinal Chemistry, 55(7), 3452-3478; 2012; international PCTapplication publication, WO 2008/016131; each of which is incorporatedherein by reference.

In an exemplary synthesis of a compound of Formula (I), a compound ofFormula 1 is reacted with a compound of Formula 2. The leaving group LG¹of the compound of Formula 2 is displaced by the nucleophilic aminomoiety of the compound of Formula 1 to give a compound of Formula 3,which is a compound of Formula (I) where R^(C) is H. The compound ofFormula 3 undergoes a nucleophilic displacement reaction with a compoundof Formula 4 that includes leaving group LG², yielding a compound ofFormula 5, which is a compound of Formula (I) where R^(C) is not H.Alternatively, a compound of Formula 1 may react with a compound ofFormula 4, and the resulting product may react with a compound ofFormula 2 to yield a compound of Formula 5.

In another exemplary synthesis of a compound of Formula (I) (e.g., acompound of Formula 11 in Scheme 2 below) where Ring A includes anitrogen atom, a compound of Formula 1 reacts with a compound of Formula8, which includes leaving group LG³, and the reaction product reactswith a compound of Formula 4 to give a compound of Formula 9 (Scheme 2).A compound of Formula 9 may alternatively be prepared by reacting acompound of Formula 1 with a compound of Formula 4 and reacting theresulting product with a compound of Formula 8. A compound of Formula10, which includes a nucleophilic secondary amino moiety, displaces LG³of the compound of Formula 9 to furnish the compound of Formula 11. Acompound of Formula 11 may alternatively be synthesized by reacting acompound of formula 1 with a compound of Formula 8, followed by areaction with a compound of Formula 10 and then by a reaction with acompound of Formula 4.

Following are examples of the synthesis of exemplary compounds ofFormula (I), starting from compound 6.

Example 1. Preparation of Compound I-1

N-(5-(2-Aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(compound 6, 189 mg, 0.5 mmol) was dissolved in dichloromethane.2-(Oxetan-3-yl)acetic acid (87 mg, 0.75 mmol) was added followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI, 155 mg, 1.0 mmol)and 4-dimethylaminopyridine (DMAP, 5 mg). The resulting mixture wasstirred for 3 hours, diluted with ethyl acetate (25 mL), and washed withsaturated sodium bicarbonate (10 mL). The organic phase was separated,dried with anhydrous magnesium sulfate, and evaporated. The resultingresidue was purified by flash chromatography eluting with a gradientfrom ethyl acetate to ethyl acetate-methanol (70:30). The fractions wereconcentrated, and the resulting residue was suspended in dichloromethane(1 mL) and diethyl ether (20 mL) was added. The resulting precipitatewas filtered and dried in high vacuum to yield compound I-1 as a whitesolid (82 mg). MS: m/z 476.3 (M+1) (positive ionization mode). ¹H NMR:(DMSO-d6): 10.85 (s, 1H), 9.78 (s, 1H), 8.01 (d, J=9.5 Hz, 1H), 7.92 (s,1H), 7.33 (s, J=8.5 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H), 7.08 (dd, J=8.5,2.5 Hz, 1H), 7.03 (d, J=9.5 Hz, 1H), 6.80 (s, 1H), 4.67 (dd, J=6.0, 7.5Hz, 2H), 4.31 (dd, J=6.0, 6.0 Hz, 2H), 3.96 (s, 3H), 3.40-3.25 (m, 2H),2.77 (d, J=8.0 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H).

Example 2. Preparation of Compound I-2

N-(5-(2-Aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(compound 6, 189 mg, 0.5 mmol) was dissolved in tetrahydrofuran.Triethylamine (0.5 mL, 3.5 mmol) was added followed by chloroacetylchloride (96 mg, 0.85 mmol), then the resulting mixture was stirred for1 hour to generate intermediate 12. (S)-N,N-dimethylpyrrolidin-3-amine(171 mg, 1.5 mmol) was added. The resulting mixture was heated to 60° C.for 2 hours. The volatiles were evaporated, and the residue wasdissolved in dichloromethane (25 mL) and washed with saturated sodiumbicarbonate (10 mL). The organic phase was directly purified by flashchromatography eluted with a gradient from dichloromethane todichloromethane-methanol-triethylamine (80:10:10). The fractions wereconcentrated, leaving a yellow foam (200 mg). Further purification wasperformed using reverse phase chromatography (8-gram C₁₈ column,gradient from 5:95 water-acetonitrile to 95:5 water-acetonitrile; bothwater and acetonitrile contained 0.01% of formic acid modifier). Theproduct obtained from the reverse phase chromatography was converted tofree base using dichloromethane-aqueous sodium bicarbonate, dried withsodium sulfate, and concentrated. Hexane was added to the resultingresidue to precipitate out compound I-2 as a yellow solid (15 mg). MSm/z: 532.3 (M+1) (positive ionization mode). ¹H NMR: (DMSO-d6): 10.33(s, 1H), 9.79 (s, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.98 (s, 2H), 7.33 (d,J=8.5 Hz, 1H) 7.26 (d, J=2.5 Hz, 1H), 7.08 (dd, J=2.5, 8.5 Hz, 1H), 7.05(d, J=9.5 Hz, 1H) 6.80 (s, 1H), 3.96 (s, 3H), 3.31 (d, J=15.5 Hz, 1H),3.21 (d, J=15.5 Hz, 1H), 2.79-2.60 (m, 4H), 2.59-2.53 (m, 1H), 2.48-2.40(m, 1H), 2.34 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H). 1.89-1.80 (m, 1H),1.66-1.58 (m, 1H).

Example 3. Preparation of Compound I-3

Compound I-3 was prepared in the same manner as compound I-2 except that(R)-N,N-dimethylpyrrolidin-3-amine was used instead of(S)-N,N-dimethylpyrrolidin-3-amine. Compound I-3 was obtained as ayellow solid (32 mg). MS: m/z 532.3 (M+1) (positive ionization mode). ¹HNMR: (DMSO-d6): 10.35 (s, 1H), 9.79 (s, 1H), 8.14-7.79 (m, 2H),7.37-7.26 (m, 2H), 7.12-7.02 (m, 2H). 6.80 (s, 1H), 3.96 (s, 3H),3.42-3.16 (m, 2H), 2.79-2.60 (m, 4H), 2.59-2.53 (m, 1H), 2.48-2.40 (m,1H), 2.34 (s, 3H), 2.17 (s, 3H), 2.09 (s, 3H), 1.89-1.80 (m, 1H),1.66-1.58 (m, 1H).

Example 4. Preparation of Compound I-4

N-(5-(2-Aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(compound 6, 189 mg, 0.5 mmol) was dissolved in tetrahydrofuran.Triethylamine (0.3 mL, 2.1 mmol) was added followed by 4-bromobutanoylchloride (95 mg, 0.50 mmol), and the resulting mixture was stirred for 2hours to generate intermediate 13. The volatiles were evaporated, andthe residue was re-dissolved in DMF (3 mL). 2-Oxa-7-azaspiro[3.5]nonane(generated from 2-oxa-7-azaspiro[3.5]nonane hemioxalate (0.5 g, 5.8mmol) using 10M NaOH and ethyl acetate extraction) was added followed bypotassium carbonate (138 mg, 1.0 mmol). The resulting mixture was heatedto 60° C. for 3 hours. The volatiles were evaporated, and the residuewas dissolved in ethyl acetate (25 mL) and washed with saturated sodiumbicarbonate (10 mL). The organic phase was evaporated, leaving a yellowoil (239 mg). Purification was performed using reverse phasechromatography (8 gram C₁₈ column, gradient from 5:95 water-acetonitrileto 95:5 water-acetonitrile; both water and acetonitrile contained 0.01%of formic acid modifier). The obtained product was converted to freebase using dichloromethane-aqueous sodium bicarbonate, dried with sodiumsulfate, and concentrated. Hexane was added to the resulting residue toyield compound I-4 as a yellow solid (32 mg). MS: m/z 573.3 (M+1)(positive ionization mode). ¹H NMR: (DMSO-d6): 9.78 (s, 1H), 9.09 (s,1H), 7.96 (d, J=10.0 Hz, 1H), 7.68 (s, 1H), 7.32 (d, J=8.5 Hz, 1H),7.2-7.20 (m, 2H), 7.06 (dd, J=8.5, 2.5 Hz, 1H), 6.97 (d, J=10.0 Hz, 1H),6.79 (s, 1H), 4.83-4.68 (m, 3H), 4.41 (dd, J=5.5, 5.5 Hz, 2H), 3.96 (s,3H), 2.23 (s, 3H), 2.17 (s, 2.17).

Example 5. Preparation of Compound I-5

N-(5-(2-Aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide(compound 6, 189 mg, 0.5 mmol) was dissolved in dichloromethane.Triethylamine (0.5 mL, 3.5 mmol) was added. The resulting mixture wascooled to −78° C., and phosgene (0.5 mL, 15% solution in toluene, 1.0mmol) was added. The resulting mixture was stirred for 1 hour, warmed upto room temperature, and stirred further for 1 hour. 2-Oxetanyl amine(183 mg, 5.0 mmol) and DMF (3 mL) were added, and the resulting mixturewas stirred for 4 hours at 60° C. The volatiles were evaporated. Theresidue was stirred with aqueous sodium bicarbonate (10 mL), and theresulting yellow precipitate was filtered and briefly dried in highvacuum. Purification was performed using reverse phase chromatography (8gram C₁₈ column, gradient from 5:95 water-acetonitrile to 95:5water-acetonitrile; both water and acetonitrile contained 0.01% offormic acid modifier). The obtained product was converted to free baseby partitioning in dichloromethane-aqueous sodium bicarbonate, driedwith sodium sulfate, and concentrated. Hexane was added to the resultingresidue to yield compound I-5 as a yellow solid (15 mg). MS: m/z 477.2(M+1) (positive ionization mode). ¹H NMR: (DMSO-d6): 10.75 (s, 1H), 9.79(s, 1H), 8.00 (d, J=9.5 Hz, 1H), 7.95 (s, 1H), 7.33 (d, J=8.5 Hz, 1H),7.26 (d, J=2.5 Hz, 1H), 7.08 (dd, J=8.5, 2.5 Hz, 1H), 7.02 ((d, J=9.5Hz, 1H), 6.80 (s, 1H), 4.22 (s, 4H), 3.96 (s, 3H), 2.35-2.15 (m, 8H),2.24 (s, 3H), 2.18 (s, 3H), 1.85-1.65 (m, 6H).

Example 6. Preparation of Compound I-6

Compound 15

3-Amino-4-methylphenol (28.7 g, 233.3 mmol), N,N-dimethylformamide (2L), and potassium tert-butoxide (26.13 g, 232.86 mmol) were placed in a3-L round-bottom flask, purged and maintained with nitrogen. Theresulting solution was stirred for 2 hours at room temperature.tert-Butyl N-[6-iodoimidazo[1,2-b]pyridazin-2-yl]carbamate (compound 14,80 g, 222.13 mmol) was added to the reaction solution. The solution wasallowed to react, with stirring, for an additional 12 hours at 80° C.The reaction was then quenched by the addition of ice water (6 L) andthe solids were collected by filtration. The solids were washed withwater (3×500 mL) and petroleum ether (3×500 mL). This reaction wasrepeated four times and the crude product was combined (total of 600 g).This material was dissolved in tetrahydrofuran (6 L). The solution wasapplied on silica column (6 kg, 100-200 mesh). The column was elutedwith dichloromethane-tetrahydrofuran mixture (gradient from 30:1 to20:1). Fractions were analyzed by TLC(R_(f) of the product=0.5 in ethylacetate:petroleum ether 3:2). The fractions containing product werecombined and evaporated and the material was dried in vacuum for 12hours at 33° C. leaving a light yellow solid (50.0 g). The solid waswashed with ether (2×500 mL) and dried in an oven under reduced pressureto give compound 15 as a light yellow powder (39.7 g). m/z: 356.2 (M+1)(positive ionization mode).

Compound 16

tert-ButylN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(compound 15, 1.77 g, 5.0 mmol) was dissolved in tetrahydrofuran (200mL). 3-Fluorobenzoic acid (1.00 g, 7.5 mmol) was added followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.44 g, 7.5mmol) and DMAP (61 mg, 0.5 mmol). The solution was stirred overnight.The solvent was evaporated and the residue was partitioned betweensaturated sodium bicarbonate (100 mL) and ethyl acetate with 5% methanol(200 mL). The organic solution was separated and dried with magnesiumsulfate. Removal of the solvent provided compound 16 as a thick oil (2.4g) m/z: 478.6 (M+1) (positive ionization mode).

Compound 17

N-(5-(2-tert-Butoxycarbamoylimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-fluorobenzamide(compound 16, 2.4 g, 5.0 mmol) was dissolved in mixture ofdichloromethane (25 mL) and trifluoroacetic acid (25 mL). The solutionwas stirred for 1 h. The solvent was evaporated and the remainder waspartitioned between 2 M sodium hydroxide (200 mL) and 5% methanol indichloromethane (200 mL). The organic solution was separated and driedwith magnesium sulfate. The solvent was evaporated leaving compound 17as a yellow foam (1.51 g) m/z: 378.5 (M+1) (positive ionization mode).

Compound I-6

N-(5-(2-Aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-fluorobenzamide(compound 17, 1.51 g, 4.0 mmol) and lithium 2-(oxetan-3-yl)acetate (0.58g, 4.77 mmol) were dissolved in N-methylpyrrolidone (15 mL).N,N-Diisopropylethylamine (2.0 mL, 11.50 mmol) was added followed byTBTU (2.55 g, 7.94 mmol). The solution was stirred overnight. Thesolvent was evaporated and the remainder was partitioned betweensaturated sodium bicarbonate (100 mL) and 5% methanol in dichloromethane(200 mL). The organic solution was separated and dried with magnesiumsulfate. The solvent was evaporated leaving a yellow oil that waspurified by flash chromatography (Isco, 24 g column, 16 column volumes,gradient from dichloromethane to ethyl acetate). The fractions werecollected and evaporated leaving a white solid (530 mg). Furtherpurification was achieved using reverse phase flash chromatography(Isco, 120 g C18 column, gradient from 10:90 to 90:10 water-acetonitrilewith 0.1% formic acid). The fractions were collected, basified withsaturated sodium bicarbonate and the organic solvent was evaporated. Theaqueous suspension was extracted with 5% methanol in dichloromethane(200 mL), dried with magnesium sulfate and evaporated. The residue wasdissolved in ethyl acetate and slowly diluted with hexane whilesonicating. The precipitate was filtered off and dried in high vacuumovernight to yield compound I-6 as white solid (0.30 g) m/z: 476.2 (M+1)(positive ionization mode). ¹H NMR: (DMSO-d6): 10.83 (s, 1H), 10.00 (s,1H), 8.01 (d, J=10.0 Hz, 1H), 7.93 (s, 1H), 7.82-7.72 (m, 2H), 7.81-7.53(m, 1H), 7.47-7.40 (m, 1H), 7.36-7.27 (m, 2H), 7.11-7.01 (m, 2H), 4.65(dd, J=8.0, 6.0 Hz, 2H), 4.31 (dd, J=6.0, 6.0 Hz, 2H), 3.21-3.35 (m,1H), 2.71 (d, J=7.0 Hz, 2H), 2.51 (s, 3H).

Example 7. Preparation of Compound 24

Compound 22

3-(Bromomethyl)benzoic acid (1.075 g, 5.0 mmol) was dissolved indichloromethane (20 mL). Oxalyl chloride (1.26 g, 10.0 mmol) was addedfollowed by catalytic amount of N,N-dimethylformamide (0.1 mL). Thesolution was stirred for 2 h. The solvent was removed and the residuewas re-dissolved in dichloromethane (10 mL). The solvent was againremoved, leaving an oil (1.15 g). The material was dissolved indichloromethane (10 mL) and added to the solution of tert-butylN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(compound 15, 1.77 g, 5.0 mmol) dissolved in tetrahydrofuran (50 mL).The solution was stirred 1 h and piperidine (4.25 g, 50.0 mmol) wasadded. The solution was stirred 2 h. The solvent was evaporated and theresidue was partitioned between ethyl acetate and saturated sodiumbicarbonate. The organic phase was separated and dried with magnesiumsulfate. Removal of the solvent provided compound 22 as a yellow foam(2.3 g). MS: m/z 557.2 (M+1) (positive ionization mode).

Compound 23

tert-butylN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-((piperidin-1-yl)methyl)benzamidecarbamate (compound 22, 2.3 g, 4.14 mmol) was dissolved indichloromethane (20 mL). Trifluoroacetic acid (20 mL) was added and thesolution was stirred for 2 h. The solvent was evaporated and theremainder was suspended in water (50 mL) and neutralized with 10 Msodium hydroxide solution. The suspension was extracted with ethylacetate containing 10% methanol. The organic phase was separated anddried with magnesium sulfate. Removal of the solvent provided compound23 as a yellow foam (2.1 g). MS: m/z 457.2 (M+1) (positive ionizationmode).

Compound 24

N-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-((piperidin-1-yl)methyl)benzamide(crude compound 23, 2.1 g, 4.6 mmol) was dissolved in tetrahydrofuran(50 mL). Triethylamine (3.22 mL, 23.0 mmol) was added followed bycyclopropylcarbonyl chloride (478 mg, 4.6 mmol). The solution wasstirred for 2 h. The solvent was evaporated and the residue waspartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic phase was separated and dried with magnesium sulfate. Removal ofthe solvent provided crude compound 24 as a yellow foam (2.2 g).Purification was performed using flash chromatography eluting with agradient from dichloromethane to ethyl acetate with 20% methanolfollowed by ethyl acetate with 10% methanol and 10% triethylamine. Theorganic solution was evaporated and dried in high vacuum giving compound24 as a greenish amorphous foam (0.50 g). MS: m/z 525.3 (M+1) (positiveionization mode). ¹H NMR: (DMSO-d6): 11.05 (s, 1H), 9.89 (s, 1H), 8.01(d, J=9.5 Hz, 1H), 7.29 (s, 1H), 7.87-7.81 (m, 2H), 7.51-7.41 (m, 2H),7.36-7.27 (m, 2H), 7.06 (dd, J=8.5, 2.5 Hz, 1H), 7.03 (d, J=9.5 Hz, 1H),3.37 (s, 2H), 2.32 (br. s, 4H), 2.25 (s, 3H), 1.94-1.87 (m, 1H),1.51-1.43 (m, 4H), 1.41-1.31 (m, 2H), 0.81-0.75 (m, 4H).

Example 8. Preparation of Compound 27

Compound 25

Compound 25 was synthesized from 4-(bromomethyl)benzoic (1.075 g, 5.0mmol) acid and tert-butylN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(compound 15, 1.77 g, 5.0 mmol) as described for the synthesis ofcompound 22, resulting in the production of a yellow foam (3.51 g). MS:m/z 557.3 (M+1) (positive ionization mode).

Compound 26

Compound 26 was synthesized from tert-butylN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-4-((piperidin-1-yl)methyl)benzamidecarbamate (compound 25, 3.51 g) following the same procedure as thesynthesis of compound 23, resulting in a yellow foam (2.65 g). MS: m/z457.3 (M+1) (positive ionization mode).

Compound 27

Compound 27 was synthesized fromN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-4-((piperidin-1-yl)methyl)benzamide(compound 26, 2.65 g) using the procedure described for the synthesis ofcompound 24. The crude material (2.54 g) was purified by preparativeHPLC using Varian PrepStar with water-acetonitrile solvent system eachcontaining 0.1% formic acid as modifier and “Load & Lock” 50×250 mmcolumn with C18 reverse phase silica gel. The obtained solution of theproduct was converted to free base using dichloromethane with 10%methanol and aqueous sodium bicarbonate, dried with sodium sulfate, andconcentrated. The product was a yellow solid (84 mg). MS: m/z 525.3(M+1) (positive ionization mode)¹H NMR: (DMSO-d6): 11.06 (s, 1H), 9.85(s, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.95-7.87 (m, 3H), 7.40 (d, J=8.5 Hz,2H), 7.35-7.29 (m, 2H), 7.06 (dd, J=8.5, 2.5 Hz, 1H), 7.03 (d, J=9.5 Hz,1H), 3.48 (s, 2H), 2.31 (br. s, 4H), 2.25 (s, 3H), 1.95-1.87 (m, 1H),1.51-1.45 (m, 4H), 1.42-1.33 (m, 2H), 0.83-0.75 (m, 4H).

Example 9. Preparation of Compound 30

Compound 28

Compound 28 was synthesized from 2-(bromomethyl)benzoic (1.075 g, 5.0mmol) acid and tert-butylN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(compound 15, 1.77 g, 5.0 mmol) as described for the synthesis ofcompound 22, resulting in a yellow foam (5.57 g). MS: m/z 557.3 (M+1)(positive ionization mode).

Compound 29

Compound 29 was synthesized from tert-butylN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-4-((piperidin-1-yl)methyl)benzamidecarbamate (compound 28, 5.57 g) following the same procedure as thesynthesis of compound 23, resulting in a yellow foam (2.33 g). MS: m/z:457.3 (M+1) (positive ionization mode).

Compound 30

Compound 30 was synthesized fromN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-2-((piperidin-1-yl)methyl)benzamide(compound 29, 2.33 g) as described for the synthesis of compound 24. Thecrude material (2.92 g) was purified by preparative HPLC using VarianPrepStar with water-acetonitrile solvent system (each solvent containing0.1% formic acid modifier) and “Load and Lock” 50×250 mm column with C18reverse phase silica gel. The obtained solution of the product wasconverted to free base using dichloromethane with 10% methanol andaqueous sodium bicarbonate, dried with sodium sulfate, and concentrated.The product was a yellow solid (110 mg). MS: m/z 525.3 (M+1) (positiveionization mode)¹H NMR: (DMSO-d6): 11.14 (s, 1H), 10.00 (s, 1H), 8.01(d, J=9.5 Hz, 1H), 7.92 (s, 1H), 7.69-7.62 (m, 1H), 7.46-7.29 (m, 7H),7.07-7.00 (m, 2H), 3.60 (s, 2H), 2.36-2.22 (m, 7H), 1.94-1.86 (m, 1H),1.38-1.21 (m, 6H), 0.84-0.75 (m, 4H).

Example 10. Preparation of Compound 33

Compound 31

Compound 31. 3-(2-Methoxyethoxy)benzoic acid (0.975 g, 5.0 mmol) wasdissolved in dichloromethane (20 mL). Oxalyl chloride (1.26 g, 10.0mmol) was added followed by catalytic amount of N,N-dimethylformamide(0.1 mL). The solution was stirred for 2 h. The solvent was removed andthe residue was re-dissolved in dichloromethane (10 mL). The solvent wasagain removed leaving an oil (1.0 g). The material was dissolved indichloromethane (10 mL) and added to the solution of tert-butylN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(compound 15, 1.77 g, 5.0 mmol) and triethylamine (2.8 mL, 20.0 mmol)dissolved in tetrahydrofuran (50 mL). The solution was stirred 2 h. Thesolvent was evaporated and the residue was partitioned between ethylacetate and saturated sodium bicarbonate. The organic phase wasseparated and dried with magnesium sulfate. Removal of the solventprovided compound 31 as a yellow foam (2.76 g). MS: m/z 534.2 (M+1)(positive ionization mode).

Compound 32

Compound 32 was synthesized from tert-butylN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-(2-methoxyethoxy)benzamidecarbamate (compound 31, 2.76 g) following the same procedure as thesynthesis of compound 23, resulting in a yellow foam (1.70 g). MS: m/z434.3 (M+1) (positive ionization mode).

Compound 33

Compound 33 was synthesized fromN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-(2-methoxyethoxy)benzamide(compound 32, 1.70 g) as described for the synthesis of compound 24. Thecrude material (1.95 g) was purified by flash chromatography elutingwith a gradient from dichloromethane to ethyl acetate with 10% methanol.The organic solution was evaporated and dried in high vacuum givingcompound 33 as a greenish foam (1.19 g). MS: m/z 502.2 (M+1) (positiveionization mode). ¹H NMR: (DMSO-d6): 11.06 (s, 1H), 9.88 (s, 1H), 8.01(d, J=10.0 Hz, 1H), 7.93 (s, 1H), 7.56-7.49 (m, 2H), 7.41 (dd, J=8.5 Hz,8.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.29 (d, J=2.5 Hz, 1H), 7.15 (dd,J=8.0 Hz, 2.5 Hz, 1H), 7.08 (dd, J=8.5 Hz, 3.0 Hz, 1H), 7.03 (d, J=9.5Hz, 1H), 4.18-4.13 (m, 2H), 3.69-3.65 (m, 2H), 3.30 (s, 3H), 2.25 (s,3H), 1.94-1.87 (m, 1H), 0.82-0.77 (m, 4H).

Example 11. Preparation of Compound 36

Compound 34

Compound 34. 3-Benzyloxybenzoic acid (2.28 g, 10.0 mmol) was dissolvedin dichloromethane (50 mL). Oxalyl chloride (2.02 g, 20.0 mmol) wasadded followed by catalytic amount of N,N-dimethylformamide (0.2 mL).The solution was stirred for 2 h. The solvent was removed and theresidue was re-dissolved in dichloromethane (50 mL). The solvent wasagain removed leaving an oil (2.3 g). The material was dissolved indichloromethane (20 mL) and added to the solution of tert-butylN-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]carbamate(compound 15, 3.55 g, 10.0 mmol) and triethylamine (4.2 mL mL, 30.0mmol) dissolved in tetrahydrofuran (100 mL). The solution was stirredfor 2 h. The solvent was evaporated and the residue was treated withsaturated sodium bicarbonate and briefly sonicated. The precipitate wasfiltered off and washed with water. Drying in high vacuum overnightfurnished off-white solid (5.70 g). MS: m/z 566.2 (M+1) (positiveionization mode).

Compound 35

Compound 35 was synthesized from tert-butylN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-benzyloxybenzamidecarbamate (compound 34, 1.00 g) following the same procedure as thesynthesis of compound 23, resulting in a yellow foam (0.80 g). MS: m/z466.2 (M+1) (positive ionization mode).

Compound 36

Compound 36 was synthesized fromN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-benzyloxybenzamide(compound 35, 1.00 g) following the same procedure as the synthesis ofcompound 24. The crude material (0.80 g) was purified by flashchromatography (gradient from dichloromethane to ethyl acetate with 10%methanol). The organic solution was evaporated and dried in high vacuumgiving compound 36 as a greenish foam (0.31 g). MS: m/z 534.2 (M+1)(positive ionization mode). ¹H NMR: (DMSO-d6): 11.06 (s, 1H), 9.89 (s,1H), 8.01 (d, J=10.0 Hz, 1H), 7.29 (s, 1H), 7.61-7.52 (m, 2H), 7.48-7.20(m, 9H), 7.07 (dd, J=8.5 Hz, 2.5 Hz, 1H), 7.04 (d, J=10.0 Hz, 1H), 5.17(s, 2H), 2.24 (s, 3H), 1.93-1.87 (m, 1H), 0.83-0.76 (m, 4H).

Example 12. Preparation of Compound 40

Compound 37

tert-butylN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-benzyloxybenzamidecarbamate (compound 34, 1.00 g, 1.70 mmol) was dissolved inN.N-dimethylformamide (20 mL). Ammonium formate (5.00 g, 79.40 mmol) wasadded followed by palladium hydroxide (0.20 g, 20% Pd(OH)₂, wet). Thesuspension was heated at 80° C. for 3 h. The catalyst was filtered offon cellite pad and the solvent was evaporated. The residue was treatedwith saturated sodium bicarbonate and the resulting white solid wasfiltered off and washed with water. Drying in high vacuum overnight gavewhite solid (Compound 37, 1.01 g). MS: m/z 476.2 (M+1) (positiveionization mode).

Compound 38

tert-butylN-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)-3-hydroxybenzamidecarbamate (compound 37, 1.70 g, 3.57 mmol) was dissolved inN,N-dimethylformamide (50 mL). 1-(2-Chloroethyl)pyrrolidinehydrochloride (6.10 g, 35.9 mmol) was added followed by cesium carbonate(10.0 g, 30.7 mmol). The suspension was heated at 60° C. for 3 h. Thesolvent was evaporated and the remainder was partitioned between ethylacetate and brine. The organic solution was separated, dried withmagnesium sulfate and evaporated. The crude material was purified byflash chromatography using gradient of dichloromethane to ethylacetate:methanol:triethylamine 90:5:5. The solvent was evaporatedleaving yellow foam (0.53 g). MS: m/z 573.3 (M+1) (positive ionizationmode).

Compound 39

Compound 39 was synthesized from tert-butyl3-(2-(pyrrolidin-1-yl)ethoxy)-N-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)benzamidecarbamate (compound 38, 0.53 g) following the same procedure as thesynthesis of compound 23, resulting in a yellow foam (0.32 g). MS: m/z473.3 (M+1) (positive ionization mode).

Compound 40

3-(2-(Pyrrolidin-1-yl)ethoxy)-N-(5-(2-aminoimidazo[1,2-b]pyridazin-6-yloxy)-2-methylphenyl)benzamide(compound 39, 0.32 g, 0.60 mmol) was dissolved in tetrahydrofuran (10mL). Triethylamine (0.28 mL, 1.98 mmol) was added followed bycyclopropylcarbonyl chloride (68 mg, 0.66 mmol). The solution wasstirred for 1 h. The solvent was evaporated and the residue waspartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic phase was separated and dried with magnesium sulfate. Removal ofthe solvent provided crude compound a yellow foam. The crude materialwas purified by flash chromatography (gradient from dichloromethane toethyl acetate with 10% 7M ammonia in methanol). The organic solution wasevaporated and dried in high vacuum giving a yellow foam (0.18 g).Further purification was performed by preparative HPLC using VarianPrepStar with water-acetonitrile solvent system each containing 0.1%formic acid as modifier and “Load & Lock” 50×250 mm column with C18reverse phase silica gel. The obtained solution of the product wasconverted to free base using dichloromethane with 10% methanol andaqueous sodium bicarbonate, dried with sodium sulfate, and concentrated.The product was a yellow solid (86 mg). MS: m/z 541.3 (M+1), (positiveionization mode) ¹H NMR: (DMSO-d6): 11.06 (s, 1H), 9.88 (s, 1H), 8.02(d, J=9.5 Hz, 1H), 7.93 (s, 1H), 7.55-7.48 (m, 2H), 7.41 (dd, J=8.0 Hz,8.0 Hz, 1H), 7.33 (d, J=9.0 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 7.17-7.12(m, 1H), 7.08 (dd, J=8.5 Hz, 2.5 Hz, 1H), 7.03 (d, J=9.5 Hz, 1H), 4.12(t, J=6.0 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.25 (s, 3H), 1.94-1.88 (m,1H), 1.69-1.63 (m, 4H), 0.83-0.73 (m, 4H).

Example 13. Vascular Endothelial Growth Factor Receptor 2 (VEGF-R2)Cellular Assay

The Human Umbilical Endothelial (HUE) cell line expresses high levels ofVEGF-R2. Compounds of the invention are tested for the ability toinhibit tyrosine auto-phosphorylation of this receptor after stimulationwith vascular endothelial growth factor A (VEGF-A). HUE cells are platedinto 48-well cell culture plates in Endothelial Cell Growth Medium(ECGM) supplemented with 10% fetal calf serum (FCS). The cells areincubated overnight at 37° C. in Endothelial Cell Basal Medium (ECBM)supplemented with 10% FCS. On the day of the assay the compounds are 1:3serial diluted from 10 mM stocks in 100% DMSO and then 1:100 diluted toeach well of cells in ECBM without FCS to create final solutionscontaining 1% DMSO and an 8-point compound dose response curve startingat 1.0E-07 M, 1.0E-08 M, or 1.0E-09 M. Compounds of the invention areadded in duplicate to rows A, B, E, and F of the 48-well cell cultureplate. Cells in Row C are treated with 1% DMSO to serve as High control,and cells in row D are treated with 1.0E-05 M Staurosporine to serve asLow Control for the assay. Cells are incubated for 90 minutes at 37° C.in ECBM with the serial diluted compounds of the invention and thenstimulated for 3 minutes with 100 ng/ml VEGF-A. Cells are lysed, andthen levels of phosphorylated VEGF-R2 are determined in a sandwich ELISAassay formatted in a 96-well plate using a VEGF-R2 specific captureantibody and an anti-phosphotyrosine VEGF-R2 detection antibody. The rawdata are converted to percent tyrosine phosphorylated VEGF-R2 withrespect to the on plate High and Low controls. IC₅₀ values aredetermined by fitting the converted 8-point dose response data to afour-parameter logistic equation using GraphPad Prism® 5.01 software.

Example 14. Platelet-Derived Growth Factor Receptor-Beta (PDGFR-Beta)Cellular Assay

The murine embryonal fibroblast cell line NIH3T3 expresses endogenouslyhigh levels of PDGFR-beta. Compounds of the invention are tested for theability to inhibit tyrosine auto-phosphorylation of this receptor afterstimulation with platelet-derived growth factor BB (PDGF-BB). The NIH3T3cells are plated into 48-well cell culture plates in Dulbecco's ModifiedEagle Medium (DMEM) supplemented with 10% FCS. The medium is removed andthen replaced with DMEM and cells serum starved overnight at 37° C. Onthe day of the assay the compounds are 1:3 serial diluted from 10 mMstocks in 100% DMSO and then are 1:100 diluted to each well of cells inDMEM without FCS to create final DMSO solutions containing 1% DMSO andan 8-point compound dose response curve starting at 1.0E-06 M, 1.0E-07M, or 1.0E-08 M. Compounds of the invention are added in duplicate torows A, B, E, and F of the 48-well plate. Cells in Row C are treatedwith 1% DMSO to serve as High control, and cells in row D are treatedwith 1.0E-05 M Staurosporine to serve as Low Control for the assay.Cells are incubated for 90 minutes at 37° C. in DMEM with the serialdiluted compounds and then stimulated for 3 minutes with 100 ng/mlPDGF-BB. Cells are lysed, and then levels of phosphorylated PDGFR-betaare determined in a sandwich ELISA assay formatted in a 96-well plateusing a PDGFR-beta specific capture antibody and an anti-phosphotyrosinePDGFR-beta detection antibody. The raw data are converted to percentphosphorylated PDGFR-beta with respect to the on plate High and Lowcontrols. IC₅₀ values are determined by fitting the converted 8-pointdose response data to a four-parameter logistic equation using GraphPadPrism® 5.01 software.

Example 15. VEGF-R2 Binding Assay

A competition binding assay (DiscoveRx KINOMEscan™) was used to measurethe ability of the compound to compete for binding of an immobilizedadenosine triphosphosphate (ATP) site directed ligand using a DNA-taggedvascular endothelial growth receptor 2 (VEGFR2) as the target. Theability of the test compound to compete with the immobilized ligand wasmeasured using quantitative polymerase chain reaction (qPCR) of the DNAtag (Fabian, et al, Nature Biotechnology (2005) 23, 329-336; Karaman, etal, Nature Biotechnology (2008) 26, 127-132).

A VEGFR2 tagged T7 phage strain was prepared in an Escherichia coli (E.coli) derived from the BL21 strain. The E. coli were grown to log-phase,infected with VEGFR2 tagged T7 phage and then incubated with shaking at32° C. until lysis. The lysate containing the kinase was thencentrifuged and filtered to remove cell debris. Affinity resin for theVEGFR2 assay was prepared by treating Streptavidin-coated magnetic beadswith a biotinylated small molecule ligand for 30 minutes at roomtemperature. The beads were blocked with excess biotin and then washedwith blocking buffer (SeaBlock (Pierce), 1% bovine serum albumin, 0.17%phosphate buffered saline, 0.05% Tween 20, 6 mM dithiothreitol). Thebinding reaction was initiated by combining in a well of a polystyrene96-well plate, DNA tagged VEGFR2, liganded affinity beads and the serialdiluted test compound in 1× binding buffer (20% SeaBlock, 0.17×phosphate buffered saline, 0.05% Tween 20, 6 mM dithiothreitol) in afinal volume of 0.135 ml. The assay plates were incubated at roomtemperature with shaking for 1 hour and then the beads were washed withwash buffer (1× phosphate buffered saline, 0.05% Tween 20). The beadswere re-suspended in elution buffer (1× phosphate buffered saline, 0.05%Tween 20, 0.05 M non-biotinylated affinity ligand) and incubated at roomtemperature with shaking for 30 minutes. The VEGFR2 concentration in theeluate was measured using qPCR.

An 11-point dose response curve of 3-fold serial diluted test compoundstarting at 1 M was used to determine the VEGFR2 binding constant (Kd).The compounds were prepared in 100% DMSO at 100× the final testconcentration and then diluted to IX in the assay for final DMSOconcentration of 1%. Binding constants were calculated with standarddose-response curve using the Hill equation with Hill slope set to −1.Curves were fit using a non-linear least square fit with theLevenberg-Marquardt algorithm.

TABLE 3 K_(d) values of selected compounds. Compound ID K_(d) I-1 1.1I-2 1.6 I-4 1.3 I-5 1.1 I-6 0.41 24 2.5 27 1.9 30 110 33 0.44 36 6.1 401

Example 16. Novel Compounds Prepared as Mucus Penetrating Particles(MPP)

Compounds of the present invention synthesized in accordance with thepreceding Examples were formulated as mucus penetrating particles (MPP).Specifically, compounds I-2, compound I-5, and compound I-6 were eachmilled in the presence of Pluronic F127 (F127) to determine whetherF127 1) aids particle size reduction to several hundreds of nanometersand 2) physically (non-covalently) coats the surface of generatednanoparticles with a mucoinert coating that would minimize particleinteractions with mucus constituents and prevent mucus adhesion.

A milling procedure was employed in which an aqueous dispersioncontaining coarse drug particles and Pluronic F127 (F127) was milledwith grinding medium until particle size was reduced below 400 nm asmeasured by dynamic light scattering. Table 4 lists the size ofparticles and polydispersity index (a measure of the width of theparticle size distribution) generated using this technique. In thisexample suspensions were buffered using DPBS (Dulbecco'sPhosphate-Buffered Saline) which yields a suspension that is bothisotonic and has a physiologically relevant pH.

TABLE 4 Particle Size for Compounds Formulated as MPP Particle SizePolydispersity Index Compound ID (nm) (PDI) I-2 259 0.292 I-5 276 0.160I-6 245 0.206

In order to determine whether the generated nanoparticles have reducedinteractions with mucins and are therefore able to move within mucuswithout becoming trapped, particles were incubated with humancervicovaginal mucus (CVM) and observed via dark field microscopy. In atypical experiment, <1 L of the nanoparticle suspension was added to 20μl of CVM. Observations were made in a minimum of three distinct andrandomly selected areas of the CVM sample. Control particles with knownbehavior were used to qualify the CVM sample as appropriate for theassay. For compound I-5 and compound I-6, mobility in mucus was observedand therefore the nanoparticles were deemed to be effective MPP.Compound I-2 is soluble in the low pH of CVM, which is only an issue inthe assay, not in intended target sites such as the eye, which has aneutral pH.

Example 17. Compound I-2 Formulated as Solution

Solutions of I-2 were formulated with F127 or Tween 80, and under arange of pH values. Briefly, I-2 was first completely solubilized usingan acidic solution (0.1 N HCl) at a high concentration of ˜5% (w/v). Thefinal formulation was diluted to a solution consisting of 0.5% (w/v) I-2into buffered solution containing F127 or Tween 80 as described in Table5. Following dilution, the pH of the formulations was measured using pHindicator strips (PEHANON) and confirmed to be within expected range(±0.5 units of target pH).

TABLE 5 Solutions of I-2 at 0.5% (w/v) combined with solubilizers Tween80 or F127, and buffers. The values listed are final concentration ofeach constituent in the formulation. I-2 % Solubilizer % Target (w/v)(w/v) Buffer pH 0.5 Tween 80 (0.5) 20 mM Citrate 6 F127 (0.5) 20 mMCitrate 6 1x Phosphate buffered 7 saline (PBS) 20 mM Borate 8 40 mMBorate 8 20 mM Tris 8

Physical and chemical stability of the solutions at room temperature(20-25° C.) were assessed after 7-10 days (t_(final)). Physicalinstability in a solution can manifest as the precipitation andsedimentation of the drug of interest and excipients over time. Toassess physical stability, the formulations at t_(final) were firstfiltered through a 300 kDa modified polyethersulfone filter membrane(Nanosep) to remove any precipitate in the solution. The concentrationof I-2 in the filtrates was then measured and compared to that at t=0.The purity of I-2 in the unfiltered solution was also evaluated att_(final), to further confirm chemical stability. This parameter isdefined by the area under the signal peak that is attributed to compoundI-2 as a percentage of all peaks reported by in the sample by HPLC (%peak area). The content and purity results for all formulations arereported in Table 6.

TABLE 6 Chemical stability and purity of various solutions containingCompound I-2. API % API % % concen- API % Solubilizer % (w/v) at (w/v)at tration peak area at (w/v) Buffer t = 0 t = t_(final) * change ** t =t_(final) Tween 80 20 mM 0.45 0.44 −2.2 97.1 (0.5%) Citrate F127 20 mM0.52 0.50 −3.8 98.0 (0.5%) Citrate 1x PBS 0.52 0.51 −1.9 98.3 20 mM 0.540.51 −5.6 98.5 Borate 40 mM 0.52 0.52 0.0 98.5 Borate 20 mM 0.52 not de-not de- not de- Tris termined termined termined * (t_(final) = 10 daysfor formulation in Tween 80, and 7 days for formulations in F127). ** %concentration change = 100 * (API_(t=final) − API_(t=0))/API_(t=0)

The majority of the solution formulations of I-2 were physically andchemically stable, with the exception of the formulation buffered in 20mM Tris (pH 8). This formulation exhibited major physical instability(i.e., precipitation), and was not evaluated at t_(final). In all otherformulations, the concentrations of I-2 after 7-10 days storage weremaintained at >94% of their respective original concentrations measuredat t=0. The purities of I-2 in these formulations, as defined by % peakarea for all solutions, were also comparable to that of the bulk API (%peak area=98.0).

Example 18. Exposure in the Back of the Eye from Topical Administrationof Compound I-2 Solution

In order to demonstrate that topical administration of novel compoundsolution results in drug exposure at the back of the eye,pharmacokinetic (PK) studies were performed with a solution of compoundI-2 as described in Example 17. In this example, the formulationconsisted of 0.5% 1-2, 0.5% F127, in 20 mM citrate buffer pH 6.0 andNaCl (added to produce isotonic formulation). Dutch-belted rabbits weretreated with a multi-dose regimen of compound I-2 solution as shown inTable 7.

TABLE 7 Study design for PK evaluation of Compound I-2 solution Numberof Terminal Animals Time (n/time Dose Frequency/ points Group TestArticle point) Volume Duration (hours) 1 solution, 0.5% 4 50 μL BID 5days 0.5 2 solution, 0.5% 4 50 μL BID 5 days 1 3 solution, 0.5% 4 50 μLBID 5 days 2 4 solution, 0.5% 4 50 μL BID 5 days 4 5 solution, 0.5% 6 50μL BID 5 days 8 6 solution, 0.5% 6 50 μL BID 5 days 12 BID = twice a day

The resulting drug exposure in the back of the eye is shown in Table 8.The portion of the retina and choroid collected and analyzed was an 8-mmround punch where the macula is located in humans. These resultsdemonstrate that topical administration of a solution of compound I-2results in drug exposure in the retina and choroid in vivo.Draize-Ocular Irritation assessments were also performed during thesestudies and no irritation was seen for any of the formulations.

TABLE 8 PK parameters of I-2 PK Parameters Plasma Retina Choroid Tmax(hours) 0.5 0.5 2.0 Cmax (nM) 5.96 218 1790 t½ (hours) 3.63 NC NCAUC0-12 hr (nM*h) 25.6 2055 12500 Tmax: time at maximum concentration;Cmax: maximum concentration in tissue; t½: drug elimination half-life;AUC0-12 hr: the area under the curve vs. time integrated between time =0-12 hrs; NC: Not Calculated.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: X is a bond,—C(═O)—, —S(═O)—, or —S(═O)₂—; Y is a bond, —C(═O)—, —S(═O)—, or—S(═O)₂—; Ring A is substituted or unsubstituted, 7-membered, monocycliccarbocyclyl, substituted or unsubstituted, 4-membered, monocyclicheterocyclyl, substituted or unsubstituted, 7-membered, monocyclicheterocyclyl, or substituted or unsubstituted, 7- to 10-membered, spirobicyclic heterocyclyl, wherein one or two atoms in the heterocyclic ringare independently selected from the group consisting of oxygen andnitrogen; Ring Y is substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each instance of R^(A)is independently hydrogen, halogen, substituted or unsubstituted alkyl,—OR^(A1), —N(R^(A1))₂, oxo, or a nitrogen protecting group when attachedto a nitrogen atom; each instance of R^(A1) is independently hydrogen,substituted or unsubstituted alkyl, a nitrogen protecting group whenattached to a nitrogen atom, or an oxygen protecting group when attachedto an oxygen atom, or two instances of R^(A1) are joined to formsubstituted or unsubstituted heterocyclyl; a is 0, 1, 2, or 3; R^(B) issubstituted or unsubstituted alkyl or of the formula:

Ring B is substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; each instance of R^(B1) isindependently hydrogen, halogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(B1a), N(R^(B1a))₂, —SR^(B1a), —CN, —SCN,—C(═NR^(B1a))R^(B1a), —C(═NR^(B1a))OR^(B1a), —C(═NR^(B1a))N(R^(B1a))₂,—C(═O)R^(B1a), —C(═O)OR^(B1a), —C(═O)N(R^(B1a))₂, —NO₂,—NR^(B1a)C(═O)R^(B1a), —NR^(B1a)C(═O)OR^(B1a),—NR^(B1a)C(═O)N(R^(B1a))₂, —OC(═O)R^(B1a), —OC(═O)OR^(B1a),—OC(═O)N(R^(B1a))₂, or a nitrogen protecting group when attached to anitrogen atom, or two instances of R^(B1) are joined to form substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; each instance of R^(B1a) is independently hydrogen,substituted or unsubstituted acyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, a nitrogen protecting groupwhen attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two instances of R^(B1a) are joined to formsubstituted or unsubstituted heterocyclyl; b is 0, 1, 2, 3, 4, or 5;R^(C) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group; R^(D) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group; each instanceof R^(L) is independently hydrogen, halogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(L1), —N(R^(L1))₂, —SR^(L1), —CN, —SCN,—C(═NR^(L1))R^(L1), —C(═NR^(L1))OR^(L1), —C(═NR^(L1))N(R^(L1))₂,—C(═O)R^(L1), —C(═O)OR^(L1), —C(═O)N(R^(L1))₂, —NO₂,—NR^(L1)C(═O)R^(L1), —NR^(L1)C(═O)OR^(L1), —NR^(L1)C(═O)N(R^(L1))₂,—OC(═O)R^(L1), —OC(═O)OR^(L1), or —OC(═O)N(R^(L1))₂, or two instances ofR^(L) are joined to form substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each instance ofR^(L1) is independently hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(L1) are joined to form substituted or unsubstituted heterocyclyl;l is 0, 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, or
 5. 2. The compound ofclaim 1, wherein X is —C(═O)—.
 3. The compound of claim 1, wherein Y isa bond.
 4. The compound of claim 1, wherein Ring A is substituted orunsubstituted oxetanyl.
 5. The compound of claim 1, wherein Ring A is ofthe formula:


6. A The compound of claim 1, wherein R^(B) is of the formula


7. The compound of claim 6, wherein Ring B is substituted orunsubstituted phenyl.
 8. The compound of claim 6, wherein Ring B issubstituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl,wherein one, two, three, or four atoms in the heteroaryl ring isindependently selected from the group consisting of nitrogen, oxygen,and sulfur.
 9. The compound of claim 1, wherein R^(B) is of the formula:


10. The compound of claim 1, wherein m is
 1. 11. The compound of claim1, wherein m is
 3. 12. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein: U is a bond,—C(═O)—, —S(═O)—, —S(═O)₂—, —N(R^(N))—S(═O)—, or —N(R^(N))—S(═O)₂—; V isa bond, CH, CH₂, —C(═O)—, —S(═O)—, or —S(═O)₂—; W is a bond, CH₂,—S(═O)₂—, —S(═O)₂—N(R^(K))—, or

Ring Z is substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(N) is hydrogen, substitutedor unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group; R^(K) ishydrogen, substituted or unsubstituted C₁₋₆ alkyl, or a nitrogenprotecting group; R^(E) is substituted or unsubstituted alkyl or of theformula:

Ring E is substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; each instance of R^(E1) isindependently hydrogen, halogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(E1a), —N(R^(E1a))₂, —SR^(E1a), —CN, —SCN,—C(═NR^(E1a))R^(E1a), —C(═NR^(E1a))OR^(E1a), —C(═NR^(E1a))N(R^(E1a))₂,—C(═O)R^(E1a), —C(═O)OR^(E1a), —C(═O)N(R^(E1a))₂, —NO₂,—NR^(E1a)C(═O)R^(E1a), —NR^(E1a)C(═O)OR^(E1a),—NR^(E1a)C(═O)N(R^(E1a))₂, —OC(═O)R^(E1a), —OC(═O)OR^(E1a), or—OC(═O)N(R^(E1a))₂, or two instances of R^(E1) are joined to formsubstituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; each instance of R^(E1a) is independentlyhydrogen, substituted or unsubstituted acyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, a nitrogen protectinggroup when attached to a nitrogen atom, an oxygen protecting group whenattached to an oxygen atom, or a sulfur protecting group when attachedto a sulfur atom, or two instances of R^(E1a) are joined to formsubstituted or unsubstituted heterocyclyl; e is 0, 1, 2, 3, 4, or 5;R^(F) is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heterocyclyl, or a nitrogen protecting group, or R^(F) andR^(G) are joined to form a substituted or unsubstituted heterocyclicring of the formula:

Ring F is substituted or unsubstituted, 4-membered, monocyclicheterocyclyl, substituted or unsubstituted, 7-membered, monocyclicheterocyclyl, or substituted or unsubstituted, 7- to 10-membered, spirobicyclic heterocyclyl, wherein one or two atoms in the heterocyclic ringare independently selected from the group consisting of oxygen andnitrogen; each instance of R^(F1) is independently hydrogen, halogen,substituted or unsubstituted alkyl, —OR^(F1a), —N(R^(F1a))₂, oxo, or anitrogen protecting group when attached to a nitrogen atom; eachinstance of R^(F1a) is independently hydrogen, substituted orunsubstituted alkyl, or a nitrogen protecting group when attached to anitrogen atom, or an oxygen protecting group when attached to an oxygenatom, or two instances of R^(F1a) are joined to form substituted orunsubstituted heterocyclyl; f is 0, 1, 2, or 3; R^(G) is hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;R^(H) is hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group; R^(J) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group; each instanceof R^(M) is independently hydrogen, halogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(M1), —N(R^(M1))₂, —SR^(M1), —CN, —SCN,—C(═NR^(M1))R^(M1), —C(═NR^(M1))OR^(M1), —C(═NR^(M1))N(R^(M1))₂,—C(═O)R^(M1), —C(═O)OR^(M1), —C(═O)N(R^(M1))₂, —NO₂,—NR^(M1)C(═O)R^(M1), —NR^(M1)C(═O)OR^(M1), —NR^(M1)C(═O)N(R^(M1))₂,—OC(═O)R^(M1), —OC(═O)OR^(M1), or —OC(═O)N(R^(M1))₂, or two instances ofR^(M) are joined to form substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each instance ofR^(M1) is independently hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(M1) are joined to form substituted or unsubstituted heterocyclyl;p is 0, 1, 2, 3, or 4; and n is 0, 1, 2, 3, 4, or
 5. 13. The compound ofclaim 12, wherein U is a bond.
 14. The compound of claim 12, wherein Uis —C(═O)—.
 15. The compound of claim 12, wherein V is a bond.
 16. Thecompound of claim 12, wherein R^(E) is of the formula:


17. The compound of claim 12, wherein R^(F) and R^(G) are joined to forma substituted or unsubstituted heterocyclic ring of the formula:


18. The compound of claim 12, wherein n is
 0. 19. A compound representedby a formula:

or a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and optionally a pharmaceutically acceptableexcipient.
 21. A method of treating an ocular disease in a subject inneed thereof comprising: administering to the subject a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising thecompound.
 22. The method according to claim 21, wherein the oculardisease is macular degeneration, diabetic retinopathy, retinoblastoma,edema, diabetic macular edema, retinal vein occlusion, age-relatedmacular degeneration, or corneal neovascularization.
 23. The methodaccording to claim 21, wherein the compound, pharmaceutically acceptablesalt, or pharmaceutical composition is administered orally oradministered topically to the eye.